Process for the synthesis of n-(2-pyrimidinyl)piperazines catalyzed by teb ac

Abstract

This invention proposes a TEBAC-catalyzed synthesis process for N-(2-pyrimidinyl)piperazine, specifically including the following steps: Condensation reaction step: Water, anhydrous piperazine, sodium carbonate, and TEBAC are added to a reaction vessel, stirred and heated to 40-60°C, and 2-chloropyrimidine is slowly added dropwise over 1-2 hours. After the addition is complete, the reaction is maintained at the temperature and stirred for 0.5-1.5 hours. After the reaction is completed, the mixture is cooled to 20-25°C, and the insoluble sodium chloride byproduct is removed by filtration. The filtrate is extracted three times with chloroform, the organic phases are combined, and the mixture is washed once with an equal volume of deionized water. The mixture is concentrated under normal pressure to remove chloroform until no fraction flows out, yielding the crude product. Distillation and purification step: The crude product is fed into a vacuum distillation apparatus with 15-20 theoretical plates and distilled under a vacuum of -0.092 to -0.098 MPa. The low-boiling-point substances are distilled off first, and the positive-boiling-point substances are collected after the temperature at the top of the column stabilizes. The present invention shortens the heat preservation time from 4-6 hours to 0.5-1.5 hours, shortens the production cycle, improves equipment utilization, and increases the reaction rate.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a TEBAC-catalyzed process for the synthesis of N-(2-pyrimidinyl)piperazine. Background Technology

[0002] N-(2-pyrimidinyl)piperazine is an important nitrogen-containing heterocyclic pharmaceutical intermediate, widely used in the synthesis of antipsychotics (such as ziprasidone), antihistamines (such as cyproheptadine derivatives), antitumor drugs, and anxiolytics. Currently, the mainstream industrial synthesis method uses 2-chloropyrimidine and anhydrous piperazine as starting materials, carrying out a nucleophilic substitution reaction under alkaline conditions.

[0003] The existing technology has the following drawbacks: 1. Extremely low reaction efficiency: Piperazine is easily soluble in the aqueous phase but difficult to dissolve in the organic phase. The reaction only proceeds slowly at the oil-water interface. It usually requires 4 to 6 hours of heat preservation to achieve a conversion rate of about 85%. The production cycle is long and the equipment utilization rate is low.

[0004] 2. High impurity content and difficult separation: Piperazine molecules contain two secondary amine nitrogen atoms with similar chemical properties, which are prone to undergo a double substitution reaction with two molecules of 2-chloropyrimidine to generate 1,4-dipyrimidinylpiperazine. This impurity has a boiling point close to that of the main product, making it extremely difficult to separate by distillation. In existing processes, the content of this impurity is usually as high as 5% to 12%.

[0005] 3. Harsh reaction conditions: High temperatures of 75-90℃ are required to ensure the reaction proceeds fully. High temperatures lead to a loss rate of 8%-15% due to the hydrolysis and ring-opening of 2-chloropyrimidine, and a loss rate of 5%-10% due to the volatilization of piperazine. The utilization rate of raw materials is low.

[0006] 4. Complex post-processing: The reaction system is prone to severe emulsification, and the extraction and layering time is as long as 2 to 3 hours, resulting in significant product entrainment loss; some phase transfer catalysts used in the process (such as tetrabutylammonium bromide) are difficult to completely remove, affecting product quality. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to overcome the defects of the existing technology. The present invention proposes a TEBAC-catalyzed synthesis process for N-(2-pyrimidinyl)piperazine.

[0008] To solve the aforementioned technical problems, the technical solution adopted by the present invention is as follows: A TEBAC-catalyzed process for the synthesis of N-(2-pyrimidinyl)piperazine includes a nucleophilic substitution reaction using 2-chloropyrimidine and anhydrous piperazine as raw materials in the presence of a base. The product is obtained by extraction, concentration, and distillation after the reaction. The process uses benzyltriethylammonium chloride (TEBAC) as a phase transfer catalyst and carries out the condensation reaction in a pure aqueous system. The specific steps include: Condensation reaction steps: Add water, anhydrous piperazine, sodium carbonate, and TEBAC to a reaction vessel, stir and heat to 40-60°C, slowly add 2-chloropyrimidine dropwise over 1-2 hours, and after the addition is complete, keep the temperature and stir for 0.5-1.5 hours; after the reaction is complete, cool to 20-25°C, filter to remove insoluble sodium chloride byproduct, extract the filtrate three times with chloroform, combine the organic phases, wash once with an equal volume of deionized water, concentrate under normal pressure to remove chloroform until no fraction flows out, and obtain the crude product; Distillation and purification steps: The crude product is fed into a vacuum distillation apparatus with 15 to 20 theoretical plates and distilled under a vacuum of -0.092 to -0.098 MPa. The low-boiling-point substances are distilled off first, and the positive-boiling-point substances are collected after the temperature at the top of the column stabilizes to obtain N-(2-pyrimidinyl)piperazine product. The molar ratio of anhydrous piperazine, 2-chloropyrimidine, and sodium carbonate is (1.4–1.6):1:(1.0–1.1). The amount of TEBAC used is 0.3% to 0.7% of the mass of 2-chloropyrimidine.

[0009] Preferably, the amount of TEBAC used is 0.5% of the mass of 2-chloropyrimidine.

[0010] Preferably, the ratio of the volume of chloroform used in each extraction in the condensation reaction step to the mass of 2-chloropyrimidine is (4.1–4.5) mL / g.

[0011] Preferably, the reaction temperature in the condensation reaction step is 45-50°C, and the reaction time with stirring is 1 hour.

[0012] Preferably, the vacuum degree of the reduced pressure distillation in the distillation and refining step is -0.095 MPa, the collection temperature of the positive boiling point is 122-124°C, and the reflux ratio is controlled at 2:1-3:1.

[0013] Preferably, the process also includes a step of reusing the aqueous mother liquor: the aqueous mother liquor after extraction and separation in the condensation reaction step is concentrated under reduced pressure to 1 / 3 to 1 / 2 of its original volume, and anhydrous piperazine, sodium carbonate and TEBAC are added according to the raw material ratio of the fresh process, and the condensation reaction, extraction, concentration and distillation operations are repeated.

[0014] Preferably, the amount of TEBAC added during the mother liquor reuse process is 30% to 50% of the amount of TEBAC used in the fresh process, and the mother liquor can be recycled 3 to 5 times.

[0015] Preferably, the crude product contains less than or equal to 1.5% of 1,4-diamylinylpiperazine disubstituted impurities, the finished product has a purity of greater than or equal to 99.5%, and the total yield is 85% to 91%.

[0016] Compared with the prior art, the beneficial effects of the present invention are: The present invention shortens the heat preservation time from 4-6 hours to 0.5-1.5 hours, shortens the production cycle, improves equipment utilization, and increases the reaction rate.

[0017] The present invention reduces the content of disubstituted impurities from 5% to 12% to less than 1.5%, with crude product purity ≥80% and finished product purity ≥99.5%, significantly reducing the difficulty of subsequent refining and improving product purity.

[0018] The present invention reduces the reaction temperature from 75-90℃ to 40-60℃, the hydrolysis loss rate of 2-chloropyrimidine from 8%-15% to less than 1%, and the volatilization loss rate of piperazine from 5%-10% to less than 1%, thereby improving the utilization rate of raw materials.

[0019] The TEBAC of this invention has surface activity, which improves the oil-water interface state and shortens the extraction and separation time from 2-3 hours to 15-30 minutes, without emulsification. Moreover, TEBAC has excellent water solubility and can be completely removed by washing with water, without the need for additional catalyst removal steps. Attached Figure Description

[0020] The disclosure of this invention is illustrated with reference to the accompanying drawings. It should be understood that the drawings are for illustrative purposes only and are not intended to limit the scope of protection of this invention. In the drawings, the same reference numerals are used to refer to the same parts. Wherein: Figure 1 This is a flowchart of the synthesis process of N-(2-pyrimidinyl)piperazine according to the present invention. Detailed Implementation

[0021] It is readily understood that, based on the technical solution of this invention, those skilled in the art can propose various interchangeable structural methods and implementations without altering the essential spirit of the invention. Therefore, the following detailed embodiments and accompanying drawings are merely illustrative examples of the technical solution of this invention and should not be considered as the entirety of the invention or as limitations or restrictions on the technical solution of this invention.

[0022] The present invention will be further described in detail below with reference to specific embodiments. All reagents used in the following embodiments are industrial grade, and the analytical method is high performance liquid chromatography (HPLC).

[0023] Please see Figure 1 HPLC detection conditions: Chromatographic column: C18 column (250mm × 4.6mm, 5μm) Mobile phase: Methanol-Water (60:40, v / v) Flow rate: 1.0 mL / min Detection wavelength: 254nm Column temperature: 30℃ Injection volume: 20 μL Molar mass of main raw materials: Anhydrous piperazine (C4H) 10 N2): 86.14 g / mol 2-Chloropyrimidine (C4H3ClN2): 114.53 g / mol Sodium carbonate (Na₂CO₃): 105.99 g / mol TEBAC(C 13 H 22 ClN): 227.78 g / mol (2-Pyrimidinyl)piperazine (C8H) 12 N4): 164.21 g / mol Example 1: Standard Process Conditions Add 750 g of deionized water, 113 g (1.312 mol) of anhydrous piperazine, 97 g (0.915 mol) of sodium carbonate, and 0.5 g (0.0022 mol) of TEBAC to a 2000 mL four-necked flask, and stir to a temperature of 45–50 °C. At this temperature, slowly add 100 g (0.873 mol) of 2-chloropyrimidine dropwise over a constant-pressure dropping funnel over a period of 1 hour. After the addition is complete, maintain the temperature and stir the reaction mixture for 1 hour.

[0024] After the reaction was complete, the reaction solution was cooled to 20–25°C, and the insoluble sodium chloride byproduct was removed by filtration. The filtrate was transferred to a 2000 mL separatory funnel. 430 mL of chloroform was added to the filtrate, and the mixture was shaken and extracted for 5 minutes. The layers were allowed to separate for 15 minutes, and the lower chloroform layer was separated. The aqueous layer was extracted twice more with 430 mL of chloroform. All chloroform layers were combined and washed once with 500 mL of deionized water.

[0025] The washed chloroform layer was transferred to a 2000 mL four-necked flask and distilled off the chloroform under normal pressure until no fraction flowed out, yielding 140.2 g of crude product. HPLC analysis showed that the crude product contained 81.5% N-(2-pyrimidinyl)piperazine and 1.2% 1,4-diamyrimidinylpiperazine disubstituted impurities.

[0026] The crude product was placed in a 250 mL four-necked flask and connected to a vacuum distillation apparatus with 18 theoretical plates. The vacuum pump was turned on to maintain a vacuum of -0.095 MPa, and the temperature was slowly increased. The low-boiling fraction (mainly residual chloroform and a small amount of unreacted piperazine) was distilled off first. When the temperature at the top of the column stabilized at 122–124 °C, the reflux ratio was adjusted to 2.5:1, and the normal-boiling fraction was collected. The normal-boiling fraction was analyzed by HPLC and found to have a purity of 99.7%, which was the final product. A total of 114.8 g of the final product was obtained, with a total yield of 80.1% (based on 2-chloropyrimidine).

[0027] Theoretical yield calculation: 0.873 mol × 164.21 g / mol = 143.36 g Yield calculation: 114.8g ÷ 143.36g × 100% = 80.1% Example 2: TEBAC dosage was 0.3g The only difference between this embodiment and Example 1 is that the amount of TEBAC used is 0.3g (0.0013mol).

[0028] After the reaction was completed, 137.5 g of crude product was obtained. HPLC analysis showed that the crude product content was 80.8%, and the content of disubstituted impurities was 1.4%. After distillation, 111.9 g of finished product was obtained, with a yield of 78.1%.

[0029] Example 3: TEBAC dosage was 0.7g The only difference between this embodiment and Example 1 is that the amount of TEBAC used is 0.7g (0.0031mol).

[0030] After the reaction was completed, 141.0 g of crude product was obtained. HPLC analysis showed that the crude product content was 81.8%, and the content of disubstituted impurities was 1.1%. After distillation, 115.9 g of finished product was obtained, with a yield of 80.9%.

[0031] Example 4: Reaction temperature was 40℃ The only difference between this embodiment and Example 1 is that the reaction temperature is controlled at 40-45°C and the heat preservation reaction time is extended to 1.5 hours.

[0032] After the reaction was completed, 138.6 g of crude product was obtained. HPLC analysis showed that the crude product content was 81.0%, and the content of disubstituted impurities was 1.3%. After distillation, 112.9 g of finished product was obtained, with a yield of 78.8%.

[0033] Example 5: The reaction temperature was 55℃ The only difference between this embodiment and Example 1 is that the reaction temperature is controlled at 55-60℃ and the heat preservation reaction time is shortened to 0.5 hours.

[0034] After the reaction was completed, 139.2 g of crude product was obtained. HPLC analysis showed that the crude product content was 81.2%, and the content of disubstituted impurities was 1.3%. After distillation, 113.6 g of finished product was obtained, with a yield of 79.2%.

[0035] Example 6: Mother liquor reuse process (first reuse) The aqueous mother liquor extracted in Example 1 (approximately 1100 mL) was transferred to a rotary evaporator and concentrated under reduced pressure to half its original volume (approximately 550 mL). 375 g of fresh deionized water, 56.5 g (0.656 mol) of anhydrous piperazine, 48.5 g (0.457 mol) of sodium carbonate, and 0.2 g (0.0009 mol) of TEBAC were added to the concentrated mother liquor. After stirring thoroughly, the mixture was heated to 45–50 °C.

[0036] 50 g (0.437 mol) of 2-chloropyrimidine was slowly added dropwise over 0.5 hours at this temperature. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. Subsequent procedures were the same as in Example 1.

[0037] After the reaction was completed, 69.8 g of crude product was obtained. HPLC analysis showed that the crude product content was 80.7%, and the content of disubstituted impurities was 1.4%. After distillation, 56.7 g of finished product was obtained, with a yield of 79.0%.

[0038] Example 7: Mother liquor reuse process (third reuse) The aqueous mother liquor extracted in Example 6 was further concentrated and reused. The above operation was repeated, and 0.2g of TEBAC was added during the third reuse.

[0039] After the reaction was completed, 68.9 g of crude product was obtained. HPLC analysis showed that the crude product content was 79.8%, and the content of disubstituted impurities was 1.6%. After distillation, 55.2 g of finished product was obtained, with a yield of 76.9%.

[0040] Comparative Example 1: Without TEBAC Catalysis The only difference between this comparative example and Example 1 is that TEBAC is not added, and the heat preservation reaction time is extended to 4 hours.

[0041] After the reaction was completed, 121.5 g of crude product was obtained. HPLC analysis showed that the crude product content was 72.3%, and the content of disubstituted impurities was 8.7%. After distillation, 82.9 g of finished product was obtained, with a yield of 57.8%.

[0042] Comparative Example 2: TBAB replacing TEBAC The only difference between this comparative example and Example 1 is that TEBAC is replaced with an equimolar amount of 0.7 g (0.0022 mol) of tetrabutylammonium bromide (TBAB).

[0043] After the reaction was completed, 131.2 g of crude product was obtained. HPLC analysis showed that the crude product content was 76.6%, and the content of disubstituted impurities was 4.2%. After distillation, 97.9 g of finished product was obtained, with a yield of 68.3%.

[0044] Comparative Example 3: High-Temperature Catalyst-Free Process The only difference between this comparative example and Example 1 is that TEBAC is not added, the reaction temperature is raised to 80-85°C, and the reaction time is maintained at this temperature for 3 hours.

[0045] After the reaction was completed, 127.3 g of crude product was obtained. HPLC analysis showed that the crude product content was 74.0%, and the content of disubstituted impurities was 6.9%. After distillation, 88.3 g of finished product was obtained, with a yield of 61.6%.

[0046] Comparative Analysis of Examples and Comparative Examples The key parameters and results of the above embodiments and comparative examples are summarized in the table below: Comparative analysis: 1. Catalytic activity comparison: Compared with Comparative Example 1, in Example 1, at the same reaction temperature, the addition of 0.5g TEBAC shortened the holding time from 4 hours to 1 hour, and the reaction rate increased by 4 times; the product yield increased from 57.8% to 80.1%, an increase of 22.3 percentage points; and the content of disubstituted impurities decreased from 8.7% to 1.2%, a decrease of 7.5 percentage points.

[0047] 2. Catalyst Selectivity Comparison: Compared to Comparative Example 2, TEBAC in Example 1 showed significantly better catalytic performance than the commonly used TBAB. Using TEBAC increased the crude product content by 4.9 percentage points, reduced the content of disubstituted impurities by 3.0 percentage points, and increased the product yield by 11.8 percentage points. This is because the cationic structure of TEBAC is more suitable for forming stable ion pairs with piperazine anions, and it also exhibits stronger phase transfer capabilities.

[0048] 3. Effect of reaction temperature: Compared with Comparative Example 3, Example 1 achieved a higher yield (80.1% vs 61.6%) and lower impurity content (1.2% vs 6.9%) under mild conditions of 45-50°C than the high-temperature process of 80-85°C, which fully demonstrates the advantages of TEBAC in reducing reaction temperature and reducing raw material loss.

[0049] 4. Effect of Catalyst Dosage: Examples 1-3 show that good catalytic performance can be obtained when the TEBAC dosage is 0.3% to 0.7% of the 2-chloropyrimidine mass. With increasing TEBAC dosage, the yield slightly increases, and the content of disubstituted impurities slightly decreases, but the changes are not significant. Considering both cost and effect, the optimal dosage is approximately 0.5%.

[0050] 5. Mother liquor reuse effect: Examples 6-7 show that after the aqueous mother liquor is concentrated and reused, only a small amount of TEBAC needs to be added to achieve a yield and purity comparable to the fresh process. After the mother liquor is recycled three times, the yield still remains above 76%, and the content of disubstituted impurities is still below 2%, proving that the process of the present invention has good recyclability and can further reduce production costs.

[0051] Industrial scale-up description The process of this invention has been successfully scaled up to a 1000L reactor. The scaled-up process parameters are basically consistent with the laboratory-scale test, the product yield is stable at 78%–82%, and the product purity is ≥99.5%. The following points should be noted during the scale-up process: 1.2 - The dropping rate of chloropyrimidine should be adjusted according to the heat exchange capacity of the reactor to ensure that the reaction temperature is stable at 45-50℃.

[0052] 2. The extraction process should use a continuous countercurrent extraction device to improve extraction efficiency and reduce solvent consumption.

[0053] 3. The distillation process should use a continuous distillation unit to improve separation efficiency and reduce energy consumption.

[0054] Safety Precautions 1. Chloroform is toxic and has anesthetic properties. It should be handled in a fume hood while wearing protective gloves and a mask.

[0055] 2. Anhydrous piperazine is irritating; if it comes into contact with skin or eyes, rinse immediately with plenty of water.

[0056] 3. During vacuum distillation, attention should be paid to the sealing of the system to prevent vacuum leakage from causing product loss or safety accidents.

[0057] The above embodiments fully demonstrate that by introducing TEBAC as a phase transfer catalyst, the present invention has successfully solved many problems existing in the prior art, and has the advantages of fast reaction rate, low impurity content, high yield, mild conditions, and green environmental protection, making it suitable for large-scale industrial production.

[0058] The technical scope of this invention is not limited to the content described above. Those skilled in the art can make various modifications and variations to the above embodiments without departing from the technical concept of this invention, and all such modifications and variations should fall within the protection scope of this invention.

Claims

1. A TEBAC-catalyzed process for the synthesis of N-(2-pyrimidinyl)piperazine, comprising a nucleophilic substitution reaction using 2-chloropyrimidine and anhydrous piperazine as raw materials in the presence of a base, followed by extraction, concentration, and distillation to obtain the final product, characterized in that... The process uses benzyltriethylammonium chloride (TEBAC) as a phase transfer catalyst to carry out the condensation reaction in a pure aqueous system, and specifically includes the following steps: Condensation reaction steps: Add water, anhydrous piperazine, sodium carbonate, and TEBAC to a reaction vessel, stir and heat to 40-60°C, slowly add 2-chloropyrimidine dropwise over 1-2 hours, and after the addition is complete, keep the temperature and stir for 0.5-1.5 hours; after the reaction is complete, cool to 20-25°C, filter to remove insoluble sodium chloride byproduct, extract the filtrate three times with chloroform, combine the organic phases, wash once with an equal volume of deionized water, concentrate under normal pressure to remove chloroform until no fraction flows out, and obtain the crude product; Distillation and purification steps: The crude product is fed into a vacuum distillation apparatus with 15 to 20 theoretical plates and distilled under a vacuum of -0.092 to -0.098 MPa. The low-boiling-point substances are distilled off first, and the positive-boiling-point substances are collected after the temperature at the top of the column stabilizes to obtain N-(2-pyrimidinyl)piperazine product. The molar ratio of anhydrous piperazine, 2-chloropyrimidine, and sodium carbonate is (1.4–1.6):1:(1.0–1.1). The amount of TEBAC used is 0.3% to 0.7% of the mass of 2-chloropyrimidine.

2. The TEBAC-catalyzed N-(2-pyrimidinyl)piperazine synthesis process according to claim 1, characterized in that, The amount of TEBAC used is 0.5% of the mass of 2-chloropyrimidine.

3. The TEBAC-catalyzed N-(2-pyrimidinyl)piperazine synthesis process according to claim 1, characterized in that, The ratio of the volume of chloroform used in each extraction step to the mass of 2-chloropyrimidine in the condensation reaction step is (4.1–4.5) mL / g.

4. The TEBAC-catalyzed N-(2-pyrimidinyl)piperazine synthesis process according to claim 1, characterized in that, The reaction temperature in the condensation reaction step is 45-50℃, and the reaction time with stirring is 1 hour.

5. The TEBAC-catalyzed N-(2-pyrimidinyl)piperazine synthesis process according to claim 1, characterized in that, The vacuum degree of the reduced-pressure distillation in the distillation and refining step is -0.095 MPa, the collection temperature of the positive boiling point is 122-124℃, and the reflux ratio is controlled at 2:1-3:

1.

6. The TEBAC-catalyzed N-(2-pyrimidinyl)piperazine synthesis process according to claim 1, characterized in that, It also includes a step for reusing the aqueous mother liquor: the aqueous mother liquor after extraction and separation in the condensation reaction step is concentrated under reduced pressure to 1 / 3 to 1 / 2 of its original volume, and anhydrous piperazine, sodium carbonate and TEBAC are added according to the raw material ratio of the fresh process, and the condensation reaction, extraction, concentration and distillation operations are repeated.

7. The TEBAC-catalyzed N-(2-pyrimidinyl)piperazine synthesis process according to claim 1, characterized in that, The amount of TEBAC added during the mother liquor recycling process is 30% to 50% of the amount of TEBAC used in the fresh process, and the mother liquor can be recycled 3 to 5 times.

8. The TEBAC-catalyzed synthesis process for N-(2-pyrimidinyl)piperazine according to any one of claims 1-7, characterized in that, The crude product contained less than or equal to 1.5% of 1,4-diamylinylpiperazine disubstituted impurities, the finished product had a purity of greater than or equal to 99.5%, and the overall yield was 85%–91%.

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