A high-yield method for synthesizing benzylchloroquinoline

Abstract

This invention discloses a high-yield method for synthesizing benzyl chloroquinoline. The specific steps are as follows: Quinoline and benzyl chloride are mixed and refluxed under normal pressure, solvent-free, and metal-free conditions with stirring. When the viscosity of the reaction system increases to the point where the stirring rate significantly decreases or 50-70% of the quinoline is consumed, water is slowly added dropwise to the reaction system. After the addition is complete, the reflux reaction continues until the quinoline is completely consumed. Finally, the reaction solution is post-treated to obtain benzyl chloroquinoline. The benzyl chloroquinoline synthesis method provided by this invention is green and environmentally friendly, with mild reaction conditions, simple operation, no need for organic solvents and high pressure conditions, short production cycle (reaction time 6.5-9 hours), high yield (94.2-96.1%), and high product purity (86.31-88.58%). The post-treatment is simple, greatly reducing production costs and energy consumption, resulting in good economic benefits and making it very suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic compound technology, specifically relating to a method for synthesizing benzylchloroquinoline with high yield. Background Technology

[0002] Benzylquinoline chloride, also known as 1-benzylquinoline chloride or N-benzylquinoline quaternary ammonium salt, with CAS number 15619-48-4, is typically a purple-red liquid or solid. Due to the simultaneous presence of a hydrophobic aromatic ring and a hydrophilic quaternary ammonium salt group in its structure, this compound exhibits excellent surface activity and film-forming ability, making it promising for a wide range of applications in sterilization, preservation, phase-transfer catalysis, and as a precursor for functionalized ionic liquids.

[0003] Currently, there are few reported methods for the synthesis of benzylquinoline salts, and those methods have certain limitations. The main synthetic routes include: 1. Organic Solvent Method: Quinoline is reacted with benzyl chloride under reflux in organic solvents such as acetonitrile, toluene, and ethanol. While common, this method uses large amounts of volatile and toxic organic solvents, contradicting the trend towards green chemistry. It also suffers from complex post-processing, high solvent recovery costs, and environmental pollution. For example, US20230250061A1 discloses the preparation of high-value quinoline-based ionic liquids by reacting quinoline with excess benzyl chloride in methanol under room temperature and reflux conditions for several days. This route not only has extremely low reaction efficiency and an excessively long cycle, but also suffers from the inherent drawbacks of using organic solvents, making it difficult to meet the economic and efficiency requirements of industrial production.

[0004] 2. Aqueous Phase / High Pressure Method: To reduce the use of organic solvents, some studies have attempted to synthesize benzylquinoline salts in an aqueous phase (Zhen Yang, Yefei Wang, et al. Indolizine quaternary ammonium salt inhibitors, part III: insights into the highly effective low-toxicity acid corrosion inhibitor-synthesis and protection performance[J]. New Journal of Chemistry, 2019, 43, 18461). However, benzyl chloride readily hydrolyzes in water to form benzyl alcohol as a byproduct, and the hydrolysis is even more vigorous at high temperatures. To suppress hydrolysis and increase the reaction rate, some processes employ high-pressure reaction conditions. However, high-pressure operation requires sophisticated equipment, consumes a lot of energy, and poses certain safety risks, making it unsuitable for industrial-scale production.

[0005] Therefore, developing a green, environmentally friendly, mild, and industrially applicable method for synthesizing high-yield benzyl chloroquinoline has significant practical application value. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a high-yield method for synthesizing benzylchloroquinoline, which addresses the above-mentioned deficiencies in the prior art. This method does not require organic solvents, has a short production cycle, produces high-purity products, and has good economic benefits.

[0007] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows: A high-yield method for synthesizing benzyl chloroquinoline is provided, the specific steps of which are as follows: quinoline and benzyl chloride are mixed and refluxed under normal pressure, solvent-free and metal-free conditions. When the viscosity of the reaction system increases to the point that the stirring rate decreases significantly or the quinoline is consumed to the extent that 50-70% is consumed, water is slowly added dropwise to the reaction system. After the addition is complete, the reflux reaction continues until the quinoline is completely consumed. Finally, the reaction solution is post-treated to obtain benzyl chloroquinoline.

[0008] According to the above scheme, the molar ratio of quinoline to benzyl chloride is 1:1 to 1.5.

[0009] According to the above scheme, the reflux reaction is carried out under normal pressure and solvent-free conditions with stirring. The reflux reaction temperature is 100~105℃ and the reflux reaction time is 0.5~2h.

[0010] Preferably, the reflux reaction time is 1 hour.

[0011] Preferably, water is slowly added dropwise to the reaction system when 60% of the quinoline has been consumed in the reaction.

[0012] According to the above scheme, water is slowly added dropwise to the reaction system, and the total mass of water added to quinoline is 0.8~1.5:1. Preferably, it is 1.25:1.

[0013] According to the above procedure, water is slowly added dropwise to the reaction system over a period of 0.5 to 2 hours. The rate of water addition should be limited to avoid causing localized overheating of the reaction system and prolonging the reaction time.

[0014] According to the above plan, the reflux reaction time should continue for 5-6 hours.

[0015] According to the above scheme, the specific post-processing steps are as follows: first, the reaction solution is subjected to vacuum distillation to remove water, then the remaining product is extracted with petroleum ether, the lower aqueous phase is collected, and then dried to obtain the benzyl chloroquinoline product.

[0016] This invention first involves refluxing quinoline and benzyl chloride under normal pressure, solvent-free, and metal-free conditions. The solvent-free conditions, where the reactants are mixed in pure phase, significantly accelerate the initial reaction rate and prevent the hydrolysis of benzyl chloride into the byproduct benzyl alcohol in the presence of water during the initial reaction phase. This is crucial for achieving a high yield. As the reaction proceeds, the system viscosity increases, making uniform dispersion difficult, limiting mass transfer, decreasing the reaction rate, and increasing the risk of a sudden temperature rise and the probability of byproduct formation. This invention addresses this by slowly adding water dropwise at this stage and controlling the drop rate, thereby reducing the viscosity of the reaction system. This significantly reduces the viscosity, improves mass and heat transfer, ensures a more complete reaction, reduces byproducts, and further increases the yield of benzyl quinoline chloride.

[0017] The beneficial effects of this invention are as follows: the method for synthesizing benzyl chloroquinoline provided by this invention is green and environmentally friendly, with mild reaction conditions, simple operation, no need for organic solvents and high pressure conditions, short production cycle (reaction time 6.5~9h), high yield (94.2~96.1%), and high product purity (86.31~88.58%). The post-processing is simple, which greatly reduces production costs and energy consumption, has good economic benefits, and is very suitable for large-scale industrial production. Attached Figure Description

[0018] Figure 1 The liquid phase analysis spectrum is shown for the product prepared in Example 1 of this invention. Detailed Implementation

[0019] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to the accompanying drawings.

[0020] Example 1 A method for synthesizing benzylchloroquinoline with high yield, the specific steps of which are as follows: 198 g of quinoline (1.53 mol) and 230 g of benzyl chloride (1.82 mol) were added to a 1 L dry four-necked glass flask. The mixture was stirred and heated to 105 °C under normal pressure and refluxed for 1 hour. High-performance liquid chromatography (HPLC) monitoring showed that about 60% of the quinoline was consumed and the system became viscous. At this point, 250 g of deionized water was slowly added dropwise through a constant pressure funnel, controlling the dropping rate to be completed within 1 hour. After the addition was completed, the reaction was continued at 105 °C for 5 hours. The reaction was stopped when the quinoline peak of the starting material basically disappeared, as monitored by HPLC. The reaction solution was distilled under reduced pressure to remove water, yielding a dark red viscous semi-solid. 1000 mL of petroleum ether was added to the solid, and the mixture was stirred for 0.5 hours. After standing, the layers separated, and the upper petroleum ether layer was removed. The obtained red product was dried under vacuum at 55 °C to constant weight, yielding 380 g of solid with a yield of 95.0% and a benzyl chloroquinoline purity of 87.79%.

[0021] The product prepared in this example was detected by HPLC, and the HPLC chromatogram is shown below. Figure 1 As shown, the purity of benzylchloroquinoline was measured to be 87.79%. The relevant test data analysis is shown in Table 1 below.

[0022] Table 1

[0023] Example 2 A method for synthesizing benzylchloroquinoline with high yield, the specific steps of which are as follows: 198 g of quinoline (1.53 mol) and 250 g of benzyl chloride (1.98 mol) were added to a 1 L dry four-necked glass flask. The mixture was stirred and heated to 100 °C under normal pressure and refluxed for 1 hour. High-performance liquid chromatography (HPLC) monitoring showed that about 60% of the quinoline was consumed and the system became viscous. At this point, 250 g of deionized water was slowly added dropwise through a constant pressure funnel, controlling the dropping rate to be completed within 1 hour. After the addition was completed, the reaction was continued at 100 °C for 5 hours. The reaction was stopped when the quinoline peak of the starting material basically disappeared, as monitored by HPLC. The reaction solution was distilled under reduced pressure to remove water, yielding a dark red viscous semi-solid. 1000 mL of petroleum ether was added to the solid, and the mixture was stirred for 0.5 hours. After standing, the layers separated, and the upper petroleum ether layer was removed. The obtained red product was dried under vacuum to constant weight, yielding 384.4 g of solid, with a yield of 96.1% and a purity of 88.58% for benzyl chloroquinoline.

[0024] Example 3 A method for synthesizing benzylchloroquinoline with high yield, the specific steps of which are as follows: 198 g of quinoline (1.53 mol) and 287.5 g of benzyl chloride (2.27 mol) were added to a 1 L dry four-necked glass flask. The mixture was stirred and heated to 105 °C under normal pressure and refluxed for 1 hour. High-performance liquid chromatography (HPLC) monitoring showed that about 60% of the quinoline was consumed and the system became viscous. At this point, 300 g of deionized water was slowly added dropwise through a constant pressure funnel, controlling the dropping rate to be completed within 1 hour. After the addition was completed, the reaction was continued at 105 °C for 5 hours. The reaction was stopped when the quinoline peak of the starting material basically disappeared, as monitored by HPLC. The reaction solution was distilled under reduced pressure to remove water, yielding a dark red viscous semi-solid. 1000 mL of petroleum ether was added to the solid, and the mixture was stirred for 0.5 hours. After standing, the layers separated, and the upper petroleum ether layer was removed. The obtained red product was dried under vacuum to constant weight, yielding 376.4 g of solid benzyl chloroquinoline, with a yield of 94.2% and a purity of 86.31%.

[0025] Comparative Example 1 A method for synthesizing benzyl chloroquinoline, employing a conventional post-treatment water addition method, includes the following specific steps: 19.5 g quinoline (0.151 mol) and 23 g benzyl chloride (0.182 mol) were added to a 100 mL three-necked glass flask. No solvent was used. After stirring for 30 min, the temperature was raised to 105 °C and the reaction was carried out. After 1 h, the reaction solution was a dark red viscous liquid. After dissolving in 25 mL of deionized water, it was extracted twice with 30 mL of petroleum ether and evaporated to dryness. Finally, a dark red solid was obtained. The purity of benzyl chloroquinoline was 56.09%. The starting material did not react completely.

[0026] Comparative Example 2 A method for synthesizing benzyl chloroquinoline using an aqueous phase high-temperature and high-pressure process, the specific steps of which are as follows: 19.5 g quinoline (0.151 mol), 23 g benzyl chloride (0.182 mol), and 25 mL deionized water were added sequentially to a 100 mL autoclave lined with polytetrafluoroethylene. The mixture was stirred at room temperature for 30 min, then heated to 130 °C and reacted for 8 h. The maximum pressure inside the autoclave was 0.2 MPa, with no significant gas release. The reaction solution was dark red and had a faint paint-like odor. After the reaction was completed, the mixture was cooled to room temperature, depressurized, and extracted twice with 30 mL of petroleum ether. The extract was then evaporated to dryness, yielding a dark red solid with a yield of 97.4% and a benzyl chloroquinoline purity of 60.91%. Benzyl chloride underwent a hydrolysis side reaction at high temperature.

[0027] Comparative Example 3 A method for synthesizing benzyl chloroquinoline involves a high-temperature, high-pressure aqueous phase reaction in a metal reactor. The specific steps are as follows: 195g quinoline (1.51mol), 230g benzyl chloride (1.82mol), and 250mL deionized water were added sequentially to a 1L high-pressure reactor with a stainless steel inner liner. The reactor was sealed, and stirring was started. The reaction system was heated to 130℃ and the changes in pressure and temperature inside the reactor were monitored throughout the process. The temperature inside the reactor rose abnormally, reaching 160℃ and the pressure 2MPa. Benzyl chloride underwent a side reaction under iron catalysis, releasing a large amount of gas, and the reaction was incomplete.

[0028] Comparative Example 4 A method for synthesizing benzyl chloroquinoline, in which deionized water is added at the initial stage of the reaction, is described below: 198 g of quinoline (1.53 mol), 230 g of benzyl chloride (1.82 mol), and 250 mL of deionized water were added to a 1 L dry four-necked glass flask. Stirring was started, and the mixture was heated to 105 °C and refluxed at atmospheric pressure for 1 hour. At this point, the system was a homogeneous solution. HPLC monitoring showed that approximately 35% of the quinoline was consumed. The reaction was continued at 105 °C for another 5 hours. The reaction was then stopped, and the reaction solution was distilled under reduced pressure to remove water, yielding a dark red viscous substance. 1000 mL of petroleum ether was added, and the mixture was stirred for 0.5 hours. After standing and separating the layers, the upper petroleum ether layer was removed. The resulting red product was dried under vacuum at 55 °C to constant weight, yielding 372 g of solid product. The yield was 93.0%, and the purity of benzyl chloroquinoline was 78.42%. The initial presence of water accelerated the hydrolysis of benzyl chloride, significantly reducing the product purity.

[0029] Comparative Example 5 A method for synthesizing benzyl chloroquinoline, wherein the addition of water is delayed during the reaction, and the specific steps are as follows: 198 g of quinoline (1.53 mol) and 230 g of benzyl chloride (1.82 mol) were added to a 1 L dry four-necked glass flask. The mixture was stirred and heated to 105 °C under normal pressure and refluxed for 2.5 hours. At this point, the stirring was severely hampered and HPLC monitoring showed that about 85% of the quinoline was consumed in the reaction. At this point, 250 g of deionized water was slowly added dropwise through a constant pressure funnel, and the dropping rate was controlled to be completed within 1 hour. After the addition was completed, the reaction was continued at 105 °C for 5 hours. The reaction was then stopped, and the post-treatment was the same as in Example 1. 368 g of solid product was obtained, with a yield of 92.1% and a purity of 84.67%.

[0030] Comparative Example 6 A method for synthesizing benzyl chloroquinoline involves rapid addition of water during the reaction. The specific steps are as follows: 198 g of quinoline (1.53 mol) and 230 g of benzyl chloride (1.82 mol) were added to a 1 L dry four-necked glass flask. The mixture was stirred and heated to 105 °C under normal pressure and refluxed for 1 hour. HPLC monitoring showed that about 60% of the quinoline was consumed in the reaction. At this point, 250 g of deionized water was rapidly added dropwise through a constant pressure funnel over 10 minutes. After the addition was complete, the reaction was continued at 105 °C for 5 hours. The reaction was then stopped, and the post-treatment was the same as in Example 1. 373 g of solid product was obtained, with a yield of 93.3% and a purity of 85.21%.

[0031] The method for synthesizing benzyl chloroquinoline provided by this invention solves the problems of low yield, difficulty in scale-up, and insufficient product purity in traditional processes. The process conditions are mild, the operation is simple, and the controllability is strong, making it suitable for large-scale industrial production. The prepared benzyl chloroquinoline product can be widely used in pharmaceutical intermediates, catalysts, and other fields, and has high economic value and market prospects.

[0032] All the raw materials listed in this invention, as well as the upper and lower limits and ranges of the raw materials and the upper and lower limits and ranges of the process parameters (such as temperature, time, etc.), can realize this invention. Examples are not listed one by one here.

[0033] The above description is merely a preferred embodiment of the present invention, and should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A method for synthesizing benzylchloroquinoline with high yield, characterized in that, The specific steps are as follows: Quinoline and benzyl chloride are mixed and refluxed under normal pressure, without solvent or metal. When the viscosity of the reaction system increases to the point that the stirring rate decreases significantly or quinoline is consumed to the extent that 50-70% of the reaction is completed, water is slowly added dropwise to the reaction system. After the addition is completed, the reflux reaction continues until the quinoline is completely consumed. Finally, the reaction solution is post-treated to obtain benzyl quinoline chloride.

2. The method for synthesizing benzylchloroquinoline with high yield according to claim 1, characterized in that, The molar ratio of quinoline to benzyl chloride is 1:1 to 1.

5.

3. The method for synthesizing benzylchloroquinoline with high yield according to claim 1, characterized in that, The reaction was carried out under normal pressure and solvent-free conditions with stirring and reflux. The reflux temperature was 100~105℃ and the reflux time was 0.5~2h.

4. The method for synthesizing benzylchloroquinoline with high yield according to claim 3, characterized in that, The reflux reaction time is 1 hour.

5. The method for synthesizing benzylchloroquinoline with high yield according to claim 1, characterized in that, When 60% of the quinoline has been consumed in the reaction, water is slowly added dropwise to the reaction system.

6. The method for synthesizing benzylchloroquinoline with high yield according to claim 1, characterized in that, Water is slowly added dropwise to the reaction system, with the total mass of water added being 0.8 to 1.5 times the mass of quinoline.

7. The method for synthesizing benzylchloroquinoline with high yield according to claim 6, characterized in that, The total mass ratio of water added to quinoline was 1.25:

1.

8. The method for synthesizing benzylchloroquinoline with high yield according to claim 1, characterized in that, Water is slowly added dropwise to the reaction system over a period of 0.5 to 2 hours.

9. The method for synthesizing benzylchloroquinoline with high yield according to claim 1, characterized in that, The reflux reaction time continues for 5-6 hours.

10. The method for synthesizing benzylchloroquinoline with high yield according to claim 1, characterized in that, The specific post-processing steps are as follows: First, the reaction solution is subjected to vacuum distillation to remove water, then the remaining product is extracted with petroleum ether, the lower aqueous phase is collected, and then dried to obtain the benzyl chloroquinoline product.

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