Synthesis method of 1-(4-chlorphenyl) pyrazolidine-3-ketone

Abstract

The invention discloses a synthesis method of 1-(4-chlorphenyl) pyrazolidine-3-ketone, which comprises the following steps: by taking p-chlorophenylhydrazine hydrochloride and acrylamide as raw materials and toluene as a solvent, carrying out azeotropic dehydration under the normal pressure condition, cooling, adding flaky sodium hydroxide or potassium hydroxide, adding acrylamide, carrying out condensation reaction at 40-80 DEG C, filtering, washing and drying to obtain the 1-(4-chlorphenyl) pyrazolidine-3-ketone. And after the reaction is finished, acidifying, desolventizing, crystallizing and filtering to obtain the high-purity 1-(4-chlorphenyl) pyrazolidine-3-ketone. Compared with the prior art, the method provided by the invention has the following advantages: firstly, the inorganic base is adopted to replace the traditional sodium alkoxide organic base, so that the problems of flammability, danger and the like are avoided, and the reaction safety is greatly improved; process conditions are mild, operation steps are simplified, and repeated heating and cooling or negative pressure maintaining are not needed; and thirdly, the process is more environment-friendly, the molecular utilization rate is higher, by-products of alcohols are not generated compared with the traditional process, and the burden of sewage treatment is reduced. Sodium alkoxide is replaced by inorganic base, production cost is saved, and economic benefits are good.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one. Background Technology

[0002] In the prior art, several methods for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one have been disclosed. For example, patent document CN106866531A discloses a process for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one, which includes heating a p-chlorophenylhydrazine toluene solution to an azeotropic stage to remove toluene and water, setting the maximum temperature of the heating device to 90-120°C, then adding solid sodium methoxide and acrylamide, heating to 70°C and maintaining the temperature for reaction, terminating the reaction with water, adjusting the pH, removing solvent to recover toluene, cooling to crystallize, and centrifuging to obtain the product. This process involves high reaction temperatures and high energy consumption, which is not conducive to industrial production.

[0003] Patent document CN105693611A discloses a synthesis process for 1-(4-chlorophenyl)pyrazolidine-3-one, which includes using p-chlorophenylhydrazine hydrochloride as a raw material and toluene as a solvent, heating to 100-120℃ for dehydration, cooling and adding sodium methoxide and acrylamide, then heating to 80-90℃, holding at this temperature until no reflux, cooling to 65-70℃, adding water to adjust the pH, centrifuging for dehydration, washing with water, and drying to obtain the product. This process involves repeated heating and cooling, is complex, and has high reaction temperatures and high energy consumption, making it unsuitable for industrial production.

[0004] Patent document CN115417818A proposes an improved method: still using an alkali metal salt of alcohol (such as sodium methoxide) as the base, but reacting under negative pressure at 30–50°C, and continuously removing the generated alcohol and ammonia to drive the reaction to equilibrium, thereby obtaining higher yield and purity at a lower temperature and in a shorter time. However, it still has the following drawbacks: it still requires the use of sodium alkoxide-based organic bases, which are flammable and highly dangerous; it requires maintaining negative pressure conditions and additional tail gas treatment equipment, increasing equipment complexity and cost.

[0005] Feng Guangjun's master's thesis at Nanjing University of Science and Technology, titled "Research on the Synthesis Process of Pyrazolate Esters," discloses a synthesis process for 1-(4-chlorophenyl)pyrazolidine-3-one. This process uses p-chlorophenylhydrazine hydrochloride and acrylamide as raw materials, toluene as solvent, sodium alkoxide as base catalyst, and a reaction temperature of 80℃ for 6 hours. The thesis mentions that ammonia dissolution in the reaction system leads to side reactions, affecting product quality and efficiency. Although the method reduces ammonia dissolution by using the non-polar solvent toluene, it cannot eliminate residual ammonia in the system. The optimal yield of 1-(4-chlorophenyl)pyrazolidine-3-one is 91.6%, with a purity of 96.8%. Furthermore, this method involves high reaction temperature, long reaction time, and high energy consumption, which is not conducive to industrial production.

[0006] Sun Yongkun's master's thesis at Dalian University of Technology, titled "Research on Synthetic Process of Pyrazolate Esters," discloses a synthetic process for 1-(4-chlorophenyl)pyrazolidine-3-one. The process involves using chlorophenylhydrazine hydrochloride and acrylamide as raw materials, ethanol as solvent, sodium alkoxide as base catalyst, and reflux at 80°C with stirring until the chlorophenylhydrazine hydrochloride peak disappears. The yield of 1-(4-chlorophenyl)pyrazolidine-3-one is 88.5%, and the purity is 95%. However, repeating the process revealed that the actual reaction time is 15 hours. This method involves high reaction temperature, long reaction time, and high energy consumption, which is not conducive to industrial production.

[0007] In summary, existing synthetic methods generally suffer from the following drawbacks: high reaction temperatures or harsh process conditions lead to high energy consumption or complex equipment; complex operation often requires multiple heating, cooling, dehydration, or maintenance of negative pressure; the use of organic bases such as sodium alkoxides poses flammability and high safety hazards; and numerous side reactions result in limited product purity and yield. Therefore, there is an urgent need for a synthetic method that does not require organic bases, is simple to operate, operates under mild conditions, consumes less energy, is highly safe, and offers superior product yield and purity to address these problems. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the existing defects and provide a method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one, which uses solid sodium hydroxide instead of organic base, and has the characteristics of low cost, non-flammability, high yield, good safety and environmental protection; moreover, the basicity of sodium hydroxide is stronger than ammonia but weaker than organic base, and by removing the product ammonia in the reaction, the reaction equilibrium is continuously shifted, and the product is obtained in high yield, which can effectively solve the problems in the background technology.

[0009] To achieve the above objectives, the present invention provides the following technical solution: a method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one, comprising the following steps:

[0010] Step 1: Add p-chlorophenylhydrazine hydrochloride and toluene, or a weakly polar solvent such as dichloroethane, or a p-chlorophenylhydrazine toluene solution, or a dichloroethane solution to the reactor to remove water under normal pressure.

[0011] Step 2: After dehydration is complete and no water droplets fall, which takes about 6 hours, cool the reaction system to 10-40℃, add flake alkali or potassium hydroxide, stir for 10 minutes, and then add acrylamide.

[0012] Step 3: Maintain the reaction at 40-80℃ for 1-8 hours;

[0013] Step 4: After the reaction is complete, lower the temperature to about 50°C and adjust the pH to 2-5 with dilute sulfuric acid or hydrochloric acid;

[0014] Step 5: Remove toluene by heating under normal or reduced pressure until the temperature reaches approximately 82°C. Add an appropriate amount of water and continue solvent removal.

[0015] Adding an appropriate amount of water means adding an appropriate amount of water to the system until the liquid level is sufficient to submerge the stirring blades, so that the stirrer can work normally.

[0016] Step 6: Cool the system to 50°C and filter to obtain 1-(4-chlorophenyl)pyrazolidine-3-one.

[0017] Furthermore, the flake-shaped alkali is sodium hydroxide.

[0018] Furthermore, the molar ratio of the flake alkali to p-chlorophenylhydrazine hydrochloride is 1:1.5-4, preferably 1:2-2.5.

[0019] Furthermore, the molar ratio of acrylamide to p-chlorophenylhydrazine hydrochloride is 1:1-2, preferably 1:1-1.5.

[0020] Furthermore, the reaction temperature in step (3) is preferably 55-65°C.

[0021] Furthermore, the heat preservation reaction time in step (3) is preferably 2-6 hours.

[0022] Furthermore, in step (5), toluene is removed by atmospheric or vacuum distillation.

[0023] Furthermore, the yield of the obtained product is ≥90%, and the purity is ≥99%.

[0024] Compared with the prior art, the beneficial effects of the present invention are:

[0025] 1. This invention uses flake sodium hydroxide or potassium hydroxide to replace sodium alkoxide, avoiding the use of organic bases, making the reaction system more stable, eliminating the risk of flammability and explosion, and greatly improving production safety. Sodium hydroxide is more alkaline than ammonia but less alkaline than organic bases. In the reaction, it removes the product ammonia, causing the reaction equilibrium to shift continuously, resulting in a high yield of the product. At the same time, sodium hydroxide and potassium hydroxide are common inorganic bases, widely available and inexpensive, significantly reducing raw material costs compared to sodium alkoxide.

[0026] 2. This invention features a simple process, mild conditions, and low energy consumption. The entire synthesis process can be carried out under normal pressure, eliminating the need for complex negative pressure systems and multiple heating and cooling operations, thus simplifying the production process and facilitating industrial scale-up. The reaction temperature is controlled at 40–80℃, significantly lower than the commonly used high-temperature conditions of 80–120℃ in existing technologies, avoiding excessive energy consumption and equipment load. Due to the reduced number of process steps, energy consumption is lowered, production efficiency is improved, and overall industrial applicability is better. Compared with existing processes, this invention does not require maintaining negative pressure or additional alcohol and ammonia tail gas treatment equipment, further reducing equipment investment and operating costs.

[0027] 3. By employing the process of this invention, side reactions are effectively suppressed, and the reaction equilibrium shifts towards the product, thus enabling the acquisition of higher purity and yield in a shorter time. HPLC analysis shows that the purity of the product in the examples reaches ≥99%, and the yield is consistently between 90–93%, while the purity of existing sodium alkoxide methods is typically 96–97%, and the yield is only 88–89%. This demonstrates that this invention not only yields a higher quality target product but also possesses better process stability. Furthermore, this invention avoids the emissions of alcohol byproducts and tail gas treatment problems associated with sodium alkoxides. The byproduct salts are mainly sodium chloride or potassium chloride, simplifying wastewater treatment and significantly improving environmental friendliness. Attached Figure Description

[0028] Figure 1 This is a schematic diagram of the reaction in the synthesis method of the present invention;

[0029] Figure 2 The chromatogram of the standard 1-(4-chlorophenyl)pyrazolidine-3-one of this invention;

[0030] Figure 3 This is an HPLC chromatogram of the sample obtained in this invention. Detailed Implementation

[0031] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention.

[0032] Example 1

[0033] Please see Figure 1-3 The present invention provides a technical solution: a method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one;

[0034] 1. Add 2.29 kmol of p-chlorophenylhydrazine hydrochloride and 2500 kg of toluene to a four-necked reaction flask equipped with a mechanical stirrer, condenser and thermometer. Perform water separation under normal pressure until no more water droplets are precipitated in the separator (about 6 hours) to obtain an anhydrous p-chlorophenylhydrazine toluene solution.

[0035] 2. Cool the reaction system to 10–40℃, add 4.75kmol of flake sodium hydroxide, and stir until homogeneous for about 10 min; then add 3.35kmol of acrylamide, and keep the reaction at 40–80℃ for 1–8 h, preferably at 55–65℃ for 2–6 h.

[0036] 3. After the central control test is qualified, cool the reaction system to 50℃ and slowly add dilute sulfuric acid to adjust the pH to 2–5.

[0037] 4. Distill off toluene by heating to atmospheric pressure or reducing pressure. When the distillation temperature reaches about 82°C, add an appropriate amount of water to make the liquid level higher than the stirring blades to ensure normal stirring operation. Continue to remove the solvent until the toluene is basically removed.

[0038] 5. Cool the system to 50°C, filter and separate to obtain a solid product, and dry to obtain 1-(4-chlorophenyl)pyrazolidine-3-one.

[0039] Comparative Example 1

[0040] Using the existing technology CN106866531A, a toluene solution of p-chlorophenylhydrazine is used as raw material, and solid sodium methoxide and acrylamide are used as reaction raw materials. The reaction is carried out at 70°C, followed by acidification, solvent removal, and crystallization to obtain the product.

[0041] As attached Figure 1 As shown, p-chlorophenylhydrazine and acrylamide undergo a cyclization reaction in the presence of solid sodium hydroxide to generate the target product 1-(4-chlorophenyl)pyrazolidine-3-one. This schematic diagram visually illustrates the core technical solution of the present invention: by using an inorganic base (such as sodium hydroxide) instead of a traditional organic base (such as sodium alkoxide), the product can be synthesized efficiently, with significant advantages in safety, yield, and cost control.

[0042] Product Testing

[0043] As attached Figure 2 As shown: The product obtained by reversed-phase high-performance liquid chromatography (HPLC) is: the standard shows a single main peak at a retention time of about 4.45 min, with a purity of 99.34%.

[0044] As attached Figure 3 As shown: The product of Example 1 exhibits a single main peak at a retention time of approximately 9.52 min, with a purity of 99.12%.

[0045] Comparison with the standard showed that the product obtained in Example 1 was 1-(4-chlorophenyl)pyrazolidine-3-one with a purity of ≥99%.

[0046] Compared to the comparative process, the method of this invention can achieve the reaction at a lower reaction temperature, the process is simple to operate, avoids the use of flammable organic bases, has high production safety, and the obtained product has higher purity, making it more suitable for industrial production.

[0047] To verify the superiority of the method of the present invention, comparative experiments were conducted on different types of alkali, different reaction conditions, and batch-to-batch stability. The results are as follows.

[0048] I. Comparative Experiments with Different Bases

[0049] Under the same process conditions, sodium hydroxide and potassium hydroxide were used as alkali sources respectively to investigate the yield and purity of the products; the test results are shown in Table 1.

[0050] Table 1 Effects of different bases on the products

[0051]

[0052] The results showed that both inorganic bases could efficiently produce the target product, but the process was more stable and the purity of the product was slightly higher when sodium hydroxide was used, making it more suitable for industrial production.

[0053] II. Comparative Experiments under Different Temperatures and Molar Ratios

[0054] Under the same conditions, the effects of reaction temperature and the amount of flake alkali (relative to the molar ratio of p-chlorophenylhydrazine hydrochloride) on the reaction results were investigated; the results are shown in Table 2.

[0055] Table 2 Effects of different temperatures and molar ratios on the products

[0056]

[0057] The results showed that when the reaction temperature was controlled at 55–65℃ and the molar ratio of alkali to p-chlorophenylhydrazine hydrochloride was controlled at 2.0–2.5:1, the yield and purity of the product reached the optimal level. Compared with the prior art, this optimized condition can obtain high purity and high yield under milder conditions, showing significant technological progress.

[0058] III. Repeated Experiments (Batch-to-Batch Stability)

[0059] Under the same optimized process conditions, five batches of the reaction were carried out consecutively, and the yield and purity of the product were tested. The results are shown in Table 3.

[0060] Table 3. Inter-batch stability data

[0061] Batch number Yield (%) purity(%) Batch 1 92.1 99 Batch 2 91.8 99.2 Batch 3 92.3 99.1 Batch 4 92 99.1 Batch 5 92.2 99.2

[0062] The results show that the yield and purity of the method of the present invention have very small fluctuations (relative standard deviation RSD < 0.5%) in multiple batch experiments, proving that the process is stable and reliable and has good prospects for industrial application.

[0063] IV. Conclusion

[0064] The above comparative experiments show that:

[0065] This invention can achieve the synthesis of the target product under different alkaline conditions, with the best results under sodium hydroxide conditions;

[0066] The preferred reaction temperature and molar ratio range of this invention are indeed optimal conditions that can significantly improve yield and purity;

[0067] The method of this invention has shown high stability in multiple batches of repeated experiments, further demonstrating the reliability and industrializability of the process.

[0068] The foregoing has shown and described the basic principles, main features and advantages of the present invention. Various changes and modifications can be made to the present invention without departing from the spirit and scope thereof, and all such changes and modifications fall within the scope of the present invention as claimed.

Claims

1. A method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one, characterized in that, Includes the following steps: Step 1: Add p-chlorophenylhydrazine hydrochloride and toluene, or dichloroethane solution, or p-chlorophenylhydrazine toluene solution, or dichloroethane solution to the reactor for atmospheric pressure water separation and dehydration. Step 2: After dehydration is complete, cool the reaction system to 10-40℃, add flake alkali or potassium hydroxide, stir for 10 minutes, and then add acrylamide; Step 3: Maintain the reaction at 40-80℃ for 1-8 hours; Step 4: After the reaction is complete, lower the temperature to 50℃ and adjust the pH to 2-5 with dilute sulfuric acid or hydrochloric acid; Step 5: Remove toluene by heating under normal or reduced pressure until the temperature reaches approximately 82°C. Add an appropriate amount of water and continue solvent removal. Step 6: Cool the system to about 50°C and filter to obtain 1-(4-chlorophenyl)pyrazolidine-3-one.

2. The method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one according to claim 1, characterized in that: The flake-shaped alkali is sodium hydroxide.

3. The method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one according to claim 1, characterized in that: The molar ratio of the flake alkali to p-chlorophenylhydrazine hydrochloride is 1:1.5-4, preferably 1:2-2.

5.

4. The method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one according to claim 1, characterized in that: The molar ratio of acrylamide to p-chlorophenylhydrazine hydrochloride is 1:1-2, preferably 1:1-1.

5.

5. The method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one according to claim 1, characterized in that: The reaction temperature in step (3) is preferably 55-65℃.

6. The method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one according to claim 1, characterized in that: The preferred heat preservation reaction time in step (3) is 2-6 hours.

7. The method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one according to claim 1, characterized in that: In step (5), toluene is removed by atmospheric or vacuum distillation.

8. The method for synthesizing 1-(4-chlorophenyl)pyrazolidine-3-one according to claim 1, characterized in that: The yield of the obtained product is ≥90%, and the purity is ≥99%.

Images