Synthesis process of N-isopropyl piperazine

Abstract

The invention discloses a synthesis process of N-isopropyl piperazine, and relates to the technical field of organic synthesis, and the synthesis process comprises the following steps: step S1, adding 1-boc piperazine into acetonitrile under a stirring state; s2, adding anhydrous potassium carbonate powder into the mixed solution obtained in the step S1; s3, isopropyl bromide is pumped into the mixed solution obtained in the step S2, and the temperature is increased to 60-85 DEG C in the nitrogen atmosphere; s4, carrying out a heat preservation reaction at 70-75 DEG C, and after the reaction is finished, sequentially carrying out extraction, washing and concentration to obtain an intermediate product; s5, adding the intermediate product obtained in the step S4 into water, stirring and mixing, controlling the temperature to be 15-25 DEG C, dropwise adding hydrogen chloride, and carrying out heat preservation reaction; s6, after the reaction in the step S5 is completed, sodium hydroxide is added to control the pH value to be larger than 12, dichloromethane is added, and heat preservation and stirring are conducted; and S7, after the reaction in the step S6 is completed, sequentially extracting and concentrating to obtain a product. Isopropyl bromide is connected with a metering pump, and mixed liquid is continuously pumped, so that the process yield is improved, and byproducts are reduced.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a synthesis process of N-isopropylpiperazine. Background Art

[0002] N-isopropylpiperazine, also known as 1-isopropylpiperazine, isopropylpiperazine, etc., is an important organic compound containing a piperazine ring, in which an isopropyl group is connected to the piperazine ring. In the pharmaceutical field, isopropylpiperazine is often used as an analgesic, anesthetic and muscle relaxant. It is an important intermediate for new piperazine ring-containing type II diabetes drugs. As a derivative of the piperazine ring, it plays an important role in the production of drugs and the development of new drugs.

[0003] Therefore, N-isopropyl piperazine has a wide range of uses and a broad market prospect, but the synthesis technology content of N-isopropyl piperazine is very high, and the synthesis method of N-isopropyl piperazine mainly has several different approaches. Among them, the most common method is to prepare it by reacting piperazine with isopropyl bromide. This reaction needs to be carried out under an inert atmosphere, and usually requires the use of a high-boiling inert solvent, such as dimethyl sulfoxide or dimethylformamide. The reaction conditions are carried out at 60-80 degrees Celsius, and it usually takes several hours to complete.

[0004] However, the existing N-isopropyl piperazine synthesis cycle is long and its by-products are many. Therefore, it is urgent to provide a synthesis technique of N-isopropyl piperazine. Summary of the invention

[0005] 1. Technical issues to be solved

[0006] In view of the deficiencies of the prior art, the present invention provides a synthesis process of N-isopropylpiperazine to solve at least one technical problem raised in the background technology.

[0007] (II) Technical solution

[0008] The technical solution adopted by the present invention is:

[0009] A synthesis process of N-isopropylpiperazine comprises the following steps:

[0010] Step S1: adding 1-boc-piperazine to acetonitrile under stirring;

[0011] Step S2: adding anhydrous potassium carbonate powder to the mixed solution obtained in step S1;

[0012] Step S3: pump isopropyl bromide into the mixed solution obtained in step S2, and heat the mixture to 60-85° C. under a nitrogen atmosphere;

[0013] Step S4: keeping the temperature at 70-75° C. for reaction, and extracting, washing and concentrating the intermediate product after the reaction is completed;

[0014] Step S5: adding the intermediate product obtained in step S4 into water, stirring and mixing, adding hydrogen chloride dropwise at a temperature of 15-25° C., and keeping the temperature for reaction;

[0015] Step S6: After the reaction in step S5 is completed, sodium hydroxide is added to control the pH to be greater than 12, and dichloromethane is added, and the mixture is stirred while maintaining the temperature;

[0016] Step S7: After the reaction in step S6 is completed, the product is obtained by extraction and concentration.

[0017] Preferably, the specific steps of step S3 are:

[0018] Isopropyl bromide is connected to a metering pump at a pumping rate of 15-20 g / min.

[0019] Preferably, in step S4, during the heat preservation reaction at 70-75° C., sampling is started after 12 hours of reaction, and sampling is performed every 3-5 hours to detect the remaining amount of 1-boc piperazine, and the remaining amount of 1-boc piperazine is tracked until it is less than 0.5%; if the reaction is not complete or the change of two consecutive samples is ≤0.5%, the flow rate of pumping isopropyl bromide is increased.

[0020] Preferably, the extraction step in step S4 is as follows: after the reaction is completed, the temperature is lowered to 30-40° C., solids are removed by suction filtration, and the filter cake is rinsed with acetonitrile;

[0021] The filtrate was temperature controlled at 30-40°C, acetonitrile was concentrated to dryness under reduced pressure, methyl tert-butyl ether and purified water were added, the mixture was stirred and allowed to stand, and the aqueous phase 1 and the organic phase 1 were separated;

[0022] Methyl tert-butyl ether was added to aqueous phase 1, and the mixture was stirred and allowed to stand, and organic phase 2 was obtained by separation; and organic phase 1 and organic phase 2 were combined.

[0023] Preferably, the steps of washing and concentrating in step S4 are:

[0024] Add sodium chloride solution to the above two combined organic phases, stir and then stand, separate and take organic phase 3, control the temperature at 30-45°C and the pressure at -0.06 to -0.09 MPa to concentrate methyl tert-butyl ether until there is no fraction, and cool to 20-30°C to obtain the intermediate product.

[0025] Preferably, the dropping speed of hydrogen chloride is 80-100 kg / h, and the dropping speed is based on controlling the temperature to 15-25°C.

[0026] Preferably, the extraction step in step S7 is:

[0027] Step S6: After the reaction is completed, keep the temperature at 15-25°C, add dichloromethane and stir, and then stand to separate the liquids to obtain aqueous phase 2 and organic phase 4;

[0028] Saturated sodium chloride solution was added to the organic phase 4, stirred and allowed to stand, and the organic phase 5 was separated and heated to 20-30°C.

[0029] Preferably, the extraction step in step S7 is:

[0030] The organic phase 5 is controlled at a temperature of 20-30° C. and a pressure of -0.06 to -0.09 MPa and concentrated under reduced pressure until there is no fraction.

[0031] Preferably, in step S3, the temperature is raised to 60-85° C. under a nitrogen atmosphere at a heating rate of 20-30° C. / h.

[0032] Preferably, in the extraction process of step S4 and step S7, the product content of the aqueous phase obtained by standing and separating is tested, and if the content is > 1%, the aqueous phase is further separated.

[0033] (III) Beneficial effects

[0034] The present invention provides a synthesis process of N-isopropylpiperazine, which has the following beneficial effects compared with the prior art:

[0035] Isopropyl bromide is connected to the metering pump and continuously pumped into the mixed liquid, which can better control the temperature atmosphere of the reaction, avoid excessive heat absorption in the reaction, reduce the temperature atmosphere, and affect the later reaction process. Thereby improving the process yield and reducing by-products.

[0036] Specific implementation methods

[0037] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0038] In order to better understand the above technical solution, the above technical solution will be described in detail below in combination with specific implementation methods:

[0039] The embodiment of the present invention provides a synthesis process of N-isopropylpiperazine, comprising the following steps:

[0040] Step S1: adding 1-boc piperazine to acetonitrile under stirring, specifically, controlling the temperature at 15-25° C., and adding 1-boc piperazine to acetonitrile while stirring;

[0041] Step S2: adding anhydrous potassium carbonate powder to the mixed solution obtained in step S1;

[0042] Step S3: pump isopropyl bromide into the mixed solution obtained in step S2, and heat the mixture to 60-85° C. under a nitrogen atmosphere;

[0043] Step S4: keeping the temperature at 70-75° C. for reaction, and extracting, washing and concentrating the intermediate product after the reaction is completed;

[0044] Step S5: adding the intermediate product obtained in step S4 into water, stirring and mixing, adding hydrogen chloride dropwise at a temperature of 15-25° C., and keeping the temperature for reaction; specifically, adding the intermediate product into water at a temperature of 15-25° C.

[0045] Step S6: After the reaction in step S5 is completed, sodium hydroxide is added to control the pH to be greater than 12, and dichloromethane is added, and the mixture is stirred under heat preservation; specifically, the temperature is controlled at 15-25° C. throughout the above process;

[0046] Step S7: After the reaction in step S6 is completed, the product is obtained by extraction and concentration.

[0047] In one embodiment, the specific steps of step S3 are:

[0048] Isopropyl bromide is connected to a metering pump at a flow rate of 15-20 g / min. The above reaction absorbs heat during the dissolution reaction. If the reaction is violent, the temperature of the reaction system will drop, affecting the progress of the later reaction. By controlling the flow rate of isopropyl bromide and adding it slowly and continuously to the reaction system, it can promote a continuous forward reaction and allow the reaction raw materials to be fully mixed and contacted for reaction; it is beneficial to control the temperature of the reaction system, avoiding the temperature of the reaction system from dropping too fast under violent reactions, reducing the temperature atmosphere, and affecting the progress of the later reaction. This promotes the reaction, improves the process yield, and reduces by-products.

[0049] In one embodiment, the step S4 is carried out in a heat preservation reaction at 70-75°C, with a specific target temperature of 75°C; sampling is started after 12 hours of reaction, and sampling is performed every 3-5 hours to detect the remaining amount of 1-boc piperazine, and the remaining amount of 1-boc piperazine is tracked until it is less than 0.5%, which is when the reaction is completed; if the reaction is not complete or the change of two consecutive samples is ≤0.5%, the flow rate of the isopropyl bromide pump is increased.

[0050] In one embodiment, the extraction step in step S4 is as follows: after the reaction is completed, the temperature is lowered to 30-40° C., solids are removed by suction filtration, and the filter cake is rinsed with acetonitrile;

[0051] The filtrate was temperature controlled at 30-40°C, acetonitrile was concentrated to dryness under reduced pressure, methyl tert-butyl ether and purified water were added, the mixture was stirred and allowed to stand, and the aqueous phase 1 and the organic phase 1 were separated;

[0052] Add methyl tert-butyl ether to the aqueous phase 1, stir and then stand, separate and take the organic phase 2; combine the organic phase 1 and the organic phase 2. In the above steps, the aqueous phase is tested, and after the external standard content of the tested product is ≤1%, it is scrapped according to the three-waste treatment process. If the content is >1%, the aqueous phase is extracted once more with methyl tert-butyl ether, and the aqueous phase after extraction is scrapped according to the three-waste treatment process, and the organic phase is combined into the organic phase 1 and the organic phase 2.

[0053] In one embodiment, the steps of washing and concentrating in step S4 are:

[0054] Add sodium chloride solution to the above two combined organic phases, stir and then stand, separate and take organic phase 3, control the temperature at 30-45°C, concentrate methyl tert-butyl ether at a pressure of -0.06 to -0.09 MPa until there is no fraction, and cool to 20-30°C to obtain an intermediate product. Specifically, control the temperature at 25-30°C to add sodium chloride solution, and discard the aqueous phase produced by separation. The above temperature control at 30-45°C can be controlled by hot water.

[0055] In one embodiment, the dripping speed of hydrogen chloride is 80-100 kg / h, and the dripping speed is based on the temperature control at 15-25° C. The dripping speed and the reaction temperature are strictly controlled at 15-25° C. High temperature will produce impurities.

[0056] In one embodiment, the extraction step in step S7 is:

[0057] Step S6: After the reaction is completed, keep the temperature at 15-25°C, add dichloromethane and stir, and then stand to separate to obtain aqueous phase 2 and organic phase 4; the aqueous phase is tested to find that the product residue is ≤0.95% and then put into a barrel;

[0058] In this part, if the product residue in the water phase is not ≤ 0.95%, dichloromethane is added to the water phase 2 and stirred, and the mixture is allowed to stand for separation to obtain the organic phase 6. The organic phase 4 and the organic phase 6 are combined and a saturated sodium chloride solution is added. The mixture is allowed to stand for stirring, and the organic phase 5 is separated and heated to 20-30°C.

[0059] In one embodiment, the extraction step in step S7 is:

[0060] The organic phase 5 is temperature controlled at 20-30°C and pressure -0.06 to -0.09 MPa and concentrated under reduced pressure until there is no fraction.

[0061] In one embodiment, in step S3, the temperature is raised to 60-85° C. under a nitrogen atmosphere at a heating rate of 20-30° C. / h.

[0062] In one embodiment, in the extraction process of step S4 and step S7, the product content of the aqueous phase obtained by standing and separating is tested, and if the content is > 1%, the aqueous phase is further separated. The purpose is to achieve sufficient extraction. For example,

[0063] In the step S7, after adding dichloromethane and stirring, the mixture is allowed to stand and separate to obtain an aqueous phase and an organic phase; the aqueous phase is detected to have a product residue of ≤0.95% and then the mixture is placed in a barrel. If the aqueous phase is detected to have a product residue of ≥0.95%, the aqueous phase is added with dichloromethane and stirred, and the mixture is allowed to stand and separate to obtain an aqueous phase and an organic phase, and the aqueous phase is then detected until the aqueous phase is detected to have a product residue of ≤0.95% and then the mixture is placed in a barrel. The following is a detailed description in conjunction with a specific embodiment:

[0064] Example 1

[0065] Take 40kg acetonitrile at 20℃, start stirring, add 10kg main raw material 1-boc piperazine, 6kg anhydrous potassium carbonate powder, and connect isopropyl bromide to the metering pump at a flow rate of 20g / min. Pass a trace amount of nitrogen into the reactor to protect and prepare for heating. Heat the reactor 1 to 75℃, with a reference heating rate of 20-30℃ / h.

[0066] After heating, keep the reaction at 75℃; start sampling after 12 hours, sample once every 3 hours, and track the raw material ≤0.5%. If the reaction is not complete or the change between two consecutive samples is ≤0.5%, increase the flow rate of isopropyl bromide.

[0067] After 24 hours, the reaction was completed, the temperature was lowered to 25°C, the solid was removed by suction filtration, and the filter cake was rinsed with 50 kg of acetonitrile. The filtrate was temperature controlled at 35°C, the acetonitrile was concentrated to dryness under reduced pressure, methyl tert-butyl ether and purified water were added, stirred and allowed to stand, and the aqueous phase 1 and the organic phase 1 were separated.

[0068] Control the temperature at 35°C, add 30kg methyl tert-butyl ether and 20kg purified water to the aqueous phase 1, stir for 1h, let stand for 1h, separate the organic phase 2; combine the organic phase 1 and the organic phase 2. Put the aqueous phase into a barrel to test the external standard content of the product ≤1%, and then scrap it according to the three waste treatment process. If the content is >1%, extract the aqueous phase again with 300kg methyl tert-butyl ether. After extraction, scrap the aqueous phase according to the three waste treatment process.

[0069] Prepare sodium chloride solution with 100 kg of water and 22 kg of sodium chloride.

[0070] The temperature was controlled at 30°C, 122 kg of sodium chloride solution was added to the combined organic phase, stirred for 1 hour, allowed to stand for 1 hour, and the organic phase 3 was obtained by separation, and the aqueous phase was discarded.

[0071] The organic phase 3 was temperature controlled with hot water, and the temperature of the hot water was controlled at T = 40°C, and the methyl tert-butyl ether was concentrated at P = -0.08Mpa until there was no fraction. The system was cooled to 25°C, and a bucket was placed at the bottom of the concentration pot to weigh, and an intermediate product was obtained; the yield of the intermediate product was 96.2%.

[0072] Add 8 kg of the intermediate product to 200 kg of water at a temperature of 25°C, start stirring, control the temperature at 25°C, and dropwise add 13 kg of 12N hydrogen chloride at a rate of 90 kg / h. The rate of addition is subject to the temperature control.

[0073] After the addition is complete, the system is kept at 25°C for reaction, with the target temperature at 20°C. Sampling begins after 10 hours, and is performed every 2 hours until the raw material / (raw material + product) is ≤0.1%. If the raw material of two consecutive samples is >0.1%, and the raw material / (raw material + product) changes by ≤0.5%, additional concentrated hydrochloric acid may be added.

[0074] After the reaction is completed, add 12 kg of sodium hydroxide in batches at 25°C, stir for 1 hour, and control the pH to be above 12. Add 40 kg of dichloromethane to the system at 25°C, and keep the temperature warm and stir after the addition is completed.

[0075] Keep the temperature at 25°C, let the reaction system stand for 1 hour, separate the liquids to obtain aqueous phase 2 and organic phase 4, temporarily store aqueous phase 2 and organic phase 4.

[0076] Add 400 kg of dichloromethane to aqueous phase 2, stir for 1 hour, let stand for 1 hour, separate and take organic phase 6, combine organic phase 4 and organic phase 6, and test the aqueous phase to find that the product residue is ≤0.95% before putting it into a barrel.

[0077] Add 12 kg of saturated sodium chloride solution to the combined phase of organic phase 4 and organic phase 6, stir for 1 hour, let stand for 1 hour, separate and take organic phase 5, discard the aqueous phase, and heat organic phase 5 to 30°C. Control the temperature T = 30°C, P = -0.08 MPa, and concentrate under reduced pressure until there is no fraction to obtain the product. The final yield of N-isopropylpiperazine is 93.5%, and the purity detected by HPLC is 98.4%.

[0078] Example 2

[0079] Take 40kg acetonitrile at 25℃, start stirring, add 10kg main raw material 1-boc piperazine, 6kg anhydrous potassium carbonate powder, and connect isopropyl bromide to the metering pump at a flow rate of 20g / min. Pass a trace amount of nitrogen into the reactor to prepare for heating. Heat the reactor 1 to 85℃, target temperature 75℃, and reference heating rate 20-30℃ / h.

[0080] After heating, keep the reaction at 70℃; start sampling after 12 hours, sample once every 3 hours, and track the raw material ≤0.5%. If the reaction is not complete or the change between two consecutive samples is ≤0.5%, increase the flow rate of isopropyl bromide.

[0081] After 24 hours of reaction, the temperature was lowered to 30°C, the solid was removed by suction filtration, and the filter cake was rinsed with 50 kg of acetonitrile. The filtrate was kept at 30°C, the acetonitrile was concentrated to dryness under reduced pressure, methyl tert-butyl ether and purified water were added, stirred and allowed to stand, and the aqueous phase 1 and the organic phase 1 were separated.

[0082] Control the temperature at 30°C, add 30kg of methyl tert-butyl ether and 20kg of purified water to the aqueous phase 1, stir for 1h, let stand for 1h, separate the organic phase 2; combine the organic phase 1 and the organic phase 2. Put the aqueous phase into a barrel to test the external standard content of the product ≤1%, and then scrap it according to the three waste treatment process. If the content is >1%, extract the aqueous phase again with 300kg of methyl tert-butyl ether. After extraction, scrap the aqueous phase according to the three waste treatment process.

[0083] Prepare sodium chloride solution with 100 kg of water and 22 kg of sodium chloride.

[0084] The temperature was controlled at 25°C, 122 kg of sodium chloride solution was added to the combined organic phase, stirred for 1 hour, allowed to stand for 1 hour, and the organic phase 3 was obtained by separation, and the aqueous phase was discarded.

[0085] The organic phase 3 was temperature controlled with hot water, and the temperature of the hot water was controlled at T = 30°C, and the methyl tert-butyl ether was concentrated at P = -0.069Mpa until there was no fraction. The system was cooled to 20°C, and a bucket was placed at the bottom of the concentration pot to weigh, and the intermediate product was obtained; the yield of the intermediate product was 95.9%.

[0086] Add 8 kg of the intermediate product to 200 kg of water at a temperature of 15°C, start stirring, control the temperature at 15°C, and dropwise add 13 kg of 12N hydrogen chloride at a rate of 80 kg / h. The rate of dropwise addition is subject to the temperature control.

[0087] After the addition is complete, the system is kept at 15°C for reaction, with the target temperature at 20°C. Sampling begins after 10 hours, and is performed every hour until the raw material / (raw material + product) is ≤0.1%. If the raw material of two consecutive samples is >0.1%, and the raw material / (raw material + product) changes by ≤0.5%, additional concentrated hydrochloric acid may be added.

[0088] After the reaction is completed, add 12 kg of sodium hydroxide in batches at a temperature of 15°C, stir for 1 hour, and control the pH to be above 12. Add 40 kg of dichloromethane to the system at a temperature of 15°C, and keep the temperature and stir after the addition is complete.

[0089] Keep the temperature at 15°C, let the reaction system stand for 1 hour, separate the liquids to obtain aqueous phase 2 and organic phase 4, temporarily store aqueous phase 2 and organic phase 4.

[0090] Add 400 kg of dichloromethane to aqueous phase 2, stir for 1 hour, let stand for 1 hour, separate and take organic phase 6, combine organic phase 4 and organic phase 6, and test the aqueous phase to find that the product residue is ≤0.95% before putting it into a barrel.

[0091] Add 12 kg of saturated sodium chloride solution to the combined phase of organic phase 4 and organic phase 6, stir for 1 hour, let stand for 1 hour, separate and take organic phase 5, discard the aqueous phase, and heat organic phase 5 to 20°C. Control the temperature T = 20°C, P = -0.06 MPa, and concentrate under reduced pressure until there is no fraction to obtain the product. The final yield of N-isopropylpiperazine is 92.7%, and the purity detected by HPLC is 99.1%.

[0092] Example 3

[0093] Take 40kg acetonitrile at 25℃, start stirring, add 10kg main raw material 1-boc piperazine, 6kg anhydrous potassium carbonate powder, and connect isopropyl bromide to the metering pump at a flow rate of 15g / min. Pass a trace amount of nitrogen into the reactor to protect and prepare for heating. Heat the reactor 1 to 85℃, with a reference heating rate of 20-30℃ / h.

[0094] After heating, the target temperature is 75℃; start sampling after 12 hours, sample once every 3 hours, and track the raw material ≤0.5%. If the reaction is not complete or the change between two consecutive samples is ≤0.5%, increase the flow rate of isopropyl bromide.

[0095] After 24 hours, the reaction was completed, the temperature was lowered to 30°C, the solid was removed by suction filtration, and the filter cake was rinsed with 50 kg of acetonitrile. The filtrate was temperature controlled at 35°C, the acetonitrile was concentrated to dryness under reduced pressure, methyl tert-butyl ether and purified water were added, stirred and allowed to stand, and the aqueous phase 1 and the organic phase 1 were separated.

[0096] Control the temperature at 35°C, add 30kg methyl tert-butyl ether and 20kg purified water to the aqueous phase 1, stir for 1h, let stand for 1h, separate the organic phase 2; combine the organic phase 1 and the organic phase 2. Put the aqueous phase into a barrel to test the external standard content of the product ≤1%, and then scrap it according to the three waste treatment process. If the content is >1%, extract the aqueous phase again with 300kg methyl tert-butyl ether. After extraction, scrap the aqueous phase according to the three waste treatment process.

[0097] Prepare sodium chloride solution with 100 kg of water and 22 kg of sodium chloride.

[0098] Control the temperature at 25°C, add 122 kg of sodium chloride solution to the combined organic phase, stir for 1 hour, let stand for 1 hour, separate the liquid to obtain organic phase 3, and discard the aqueous phase

[0099] The organic phase 3 was temperature controlled with hot water, and the temperature was controlled at T = 45°C, and the methyl tert-butyl ether was concentrated at P = -0.09Mpa until there was no fraction. The system was cooled to 25°C, and a bucket was placed at the bottom of the concentration pot to weigh the intermediate product; the yield of the intermediate product was 96.8%.

[0100] Control the temperature at 15-25°C, add 8kg of the above intermediate product to 200kg of water, start stirring, control the temperature at 20°C, and drop 13kg of 12N hydrogen chloride at a rate of 90kg / h. The rate of drop is subject to the temperature control.

[0101] After the addition is complete, the system is kept at 20°C for reaction, with the target temperature at 20°C. Sampling begins after 10 hours, and is performed every 2 hours until the raw material / (raw material + product) is ≤0.1%. If the raw material of two consecutive samples is >0.1%, and the raw material / (raw material + product) changes by ≤0.5%, additional concentrated hydrochloric acid may be added.

[0102] After the reaction is completed, add 12 kg of sodium hydroxide in batches at 20°C, stir for 1 hour, and control the pH to be above 12. Add 40 kg of dichloromethane to the system at 20°C, and keep the temperature warm and stir after the addition is completed.

[0103] Keep the temperature at 20°C, let the reaction system stand for 1 hour, separate the liquids to obtain aqueous phase 2 and organic phase 4, temporarily store aqueous phase 2 and organic phase 4.

[0104] Add 400 kg of dichloromethane to aqueous phase 2, stir for 1 hour, let stand for 1 hour, separate and take organic phase 6, combine organic phase 4 and organic phase 6, and test the aqueous phase to find that the product residue is ≤0.95% before putting it into a barrel.

[0105] Add 12 kg of saturated sodium chloride solution to the combined phase of organic phase 4 and organic phase 6, stir for 1 hour, let stand for 1 hour, separate and take organic phase 5, discard the aqueous phase, and heat organic phase 5 to 25°C. Control the temperature T = 20-30°C, P = -0.09 MPa, and concentrate under reduced pressure until there is no fraction to obtain the product. The final yield of N-isopropylpiperazine is 94.7%, and the purity detected by HPLC is 98.9%.

[0106] Example 4

[0107] Take 40kg acetonitrile at 25℃, start stirring, add 10kg main raw material 1-boc piperazine, 6kg anhydrous potassium carbonate powder, and 9kg isopropyl bromide. Pass a small amount of nitrogen into the reactor to prepare for heating. Heat the reactor 1 to 85℃, with a reference heating rate of 20-30℃ / h.

[0108] After heating, the target temperature is 75℃; start sampling after 12 hours, sample once every 3 hours, and track the raw material ≤0.5%. If the reaction is not complete or the change between two consecutive samples is ≤0.5%, add isopropyl bromide.

[0109] After 36 hours, the reaction was completed, the temperature was lowered to 30°C, the solid was removed by suction filtration, and the filter cake was rinsed with 50 kg of acetonitrile. The filtrate was temperature controlled at 35°C, the acetonitrile was concentrated to dryness under reduced pressure, methyl tert-butyl ether and purified water were added, stirred and allowed to stand, and the aqueous phase 1 and the organic phase 1 were separated.

[0110] Control the temperature at 35°C, add 30kg methyl tert-butyl ether and 20kg purified water to the aqueous phase 1, stir for 1h, let stand for 1h, separate the organic phase 2; combine the organic phase 1 and the organic phase 2. Put the aqueous phase into a barrel to test the external standard content of the product ≤1%, and then scrap it according to the three waste treatment process. If the content is >1%, extract the aqueous phase again with 300kg methyl tert-butyl ether. After extraction, scrap the aqueous phase according to the three waste treatment process.

[0111] Prepare sodium chloride solution with 100 kg of water and 22 kg of sodium chloride.

[0112] The temperature was controlled at 25°C, 122 kg of sodium chloride solution was added to the combined organic phase, stirred for 1 h, allowed to stand for 1 h, and the organic phase 3 was obtained by separation, and the aqueous phase was discarded.

[0113] The organic phase 3 was temperature controlled with hot water, and the temperature of the hot water was controlled at T = 45°C, and the methyl tert-butyl ether was concentrated at P = -0.09Mpa until there was no fraction. The system was cooled to 25°C, and a bucket was placed at the bottom of the concentration pot to weigh, and the intermediate product was obtained; the yield of the intermediate product was 89.4%.

[0114] Control the temperature at 15-25°C, add 8kg of the above intermediate product to 200kg of water, start stirring, control the temperature at 20°C, and drop 13kg of 12N hydrogen chloride at a rate of 90kg / h. The rate of drop is subject to the temperature control.

[0115] After the addition is complete, the system is kept at 20°C for reaction, with the target temperature at 20°C. Sampling begins after 10 hours, and is performed every 2 hours until the raw material / (raw material + product) is ≤0.1%. If the raw material of two consecutive samples is >0.1%, and the raw material / (raw material + product) changes by ≤0.5%, additional concentrated hydrochloric acid may be added.

[0116] After the reaction is completed, add 12 kg of sodium hydroxide in batches at 20°C, stir for 1 hour, and control the pH to be above 12. Add 40 kg of dichloromethane to the system at 20°C, and keep the temperature warm and stir after the addition is completed.

[0117] Keep the temperature at 20°C, let the reaction system stand for 1 hour, separate the liquids to obtain aqueous phase 2 and organic phase 4, temporarily store aqueous phase 2 and organic phase 4.

[0118] Add 400 kg of dichloromethane to aqueous phase 2, stir for 1 hour, let stand for 1 hour, separate and take organic phase 6, combine organic phase 4 and organic phase 6, and test the aqueous phase to find that the product residue is ≤0.95% before putting it into a barrel.

[0119] Add 12 kg of saturated sodium chloride solution to the combined phase of organic phase 4 and organic phase 6, stir for 1 hour, let stand for 1 hour, separate and take organic phase 5, discard the aqueous phase, and heat organic phase 5 to 25°C. Control the temperature T = 20-30°C, P = -0.09 MPa, and concentrate under reduced pressure until there is no fraction to obtain the product. The final yield of N-isopropylpiperazine is 85.2%, and the purity detected by HPLC is 86.2%.

[0120] The above-mentioned embodiments 1-3 of the present invention all adopt the method of connecting isopropyl bromide to a metering pump and continuously pumping the mixed solution, so that the temperature atmosphere of the reaction can be better controlled, and the reaction reaction reaction reaction instantaneous heat absorption is avoided too much, and the temperature atmosphere is reduced, which affects the later reaction process. The process yield is improved and the by-products are reduced. The other process parameters of embodiment 4 are consistent with those of embodiment 3, and only the addition of isopropyl bromide is pumped in once. It can be clearly seen that the yield and purity of N-isopropylpiperazine of embodiment 1-3 are better than those of embodiment 4. And the reaction time of the first stage of embodiment 1-3 to generate the intermediate product is reduced by 12h compared with embodiment 4.

[0121] It should be noted that, in this article, the terms "comprises", "includes" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or apparatus that includes a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or apparatus.

[0122] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A synthesis process for N-isopropylpiperazine, characterized in that: The following steps are involved: Step S1: adding 1-boc-piperazine to acetonitrile under stirring; Step S2: adding anhydrous potassium carbonate powder to the mixed solution obtained in step S1; Step S3: pump isopropyl bromide into the mixed solution obtained in step S2, and heat the mixture to 60-85° C. under a nitrogen atmosphere; Step S4: keeping the temperature at 70-75° C. for reaction, and extracting, washing and concentrating the intermediate product after the reaction is completed; Step S5: adding the intermediate product obtained in step S4 into water, stirring and mixing, adding hydrogen chloride dropwise at a temperature of 15-25° C., and keeping the temperature for reaction; Step S6: After the reaction in step S5 is completed, sodium hydroxide is added to control the pH to be greater than 12, and dichloromethane is added, and the mixture is stirred while maintaining the temperature; Step S7: After the reaction in step S6 is completed, the product is obtained by extraction and concentration.

2. The synthesis process of N-isopropylpiperazine according to claim 1, characterized in that: The specific steps of step S3 are: Isopropyl bromide is connected to a metering pump at a pumping rate of 15-20 g / min.

3. The synthesis process of N-isopropylpiperazine according to claim 2, characterized in that: In the step S4, during the heat preservation reaction at 70-75° C., sampling begins after 12 hours of reaction, and sampling is performed every 3-5 hours to detect the remaining amount of 1-boc piperazine, and tracking is performed until the remaining amount of 1-boc piperazine is less than 0.5%; if the reaction is not complete or the change of two consecutive samples is ≤0.5%, the flow rate of the isopropyl bromide pump is increased.

4. The synthesis process of N-isopropylpiperazine according to claim 1, characterized in that: The extraction step in step S4 is as follows: after the reaction is completed, the temperature is lowered to 30-40° C., solids are removed by suction filtration, and the filter cake is rinsed with acetonitrile; The filtrate was temperature controlled at 30-40°C, acetonitrile was concentrated to dryness under reduced pressure, methyl tert-butyl ether and purified water were added, the mixture was stirred and allowed to stand, and the aqueous phase 1 and the organic phase 1 were separated; Methyl tert-butyl ether was added to aqueous phase 1, and the mixture was stirred and allowed to stand, and organic phase 2 was obtained by separation; and organic phase 1 and organic phase 2 were combined.

5. The synthesis process of N-isopropylpiperazine according to claim 4, characterized in that: The steps of washing and concentrating in step S4 are: Add sodium chloride solution to the above two combined organic phases, stir and then stand, separate and take organic phase 3, control the temperature at 30-45°C and the pressure at -0.06 to -0.09 MPa to concentrate methyl tert-butyl ether until there is no fraction, and cool to 20-30°C to obtain the intermediate product.

6. The synthesis process of N-isopropylpiperazine according to claim 1, characterized in that: The dropping speed of hydrogen chloride is 80-100 kg / h, and the dropping speed is based on controlling the temperature to 15-25°C.

7. The synthesis process of N-isopropylpiperazine according to claim 1, characterized in that: The extraction step in step S7 is: Step S6: After the reaction is completed, keep the temperature at 15-25°C, add dichloromethane and stir, and then stand to separate the liquids to obtain aqueous phase 2 and organic phase 4; Saturated sodium chloride solution was added to the organic phase 4, stirred and allowed to stand, and the organic phase 5 was separated and heated to 20-30°C.

8. The synthesis process of N-isopropylpiperazine according to claim 7, characterized in that: The extraction step in step S7 is: The organic phase 5 is controlled at a temperature of 20-30° C. and a pressure of -0.06 to -0.09 MPa and concentrated under reduced pressure until there is no fraction.

9. The synthesis process of N-isopropylpiperazine according to any one of claims 1 to 8, characterized in that: In the step S3, the temperature is raised to 60-85° C. under a nitrogen atmosphere at a heating rate of 20-30° C. / h.

10. The synthesis process of N-isopropylpiperazine according to any one of claims 4 or 7, characterized in that: During the extraction process of step S4 and step S7, the aqueous phase obtained by standing and separating is tested for product content. If the content is > 1%, the aqueous phase is further separated.