A method for synthesizing a highly stable 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine

Abstract

This invention provides a method for synthesizing 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. The specific synthesis steps are as follows: (1) adding n-heptaldehyde, catalyst, and water-binding agent to a reactor and stirring to mix; (2) controlling the temperature and adding aniline dropwise, and maintaining the temperature for reaction after the addition is complete; (3) washing with water, separating the layers, and removing the lower aqueous phase; (4) adding a decomposition inhibitor and then distilling under reduced pressure to obtain the product. The product content is ≥70%, and the weight loss upon heating at 100℃ / 4h is <2%.

Description

Technical Field

[0001] This invention relates to a method for synthesizing highly stable 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine, belonging to the technical field of rubber accelerators. Background Technology

[0002] 3,5-Dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine is an aldehyde-amine vulcanizing rubber accelerator. It is an environmentally friendly accelerator, particularly suitable for the thiadiazole vulcanization system of chlorinated polyethylene rubber (CM). After vulcanization, the rubber's strength, aging resistance, heat resistance, oil resistance, and flame retardancy are significantly improved. Furthermore, it can be used for the vulcanization of natural rubber, synthetic rubber, and latex. It can also be used as an activator for acidic accelerators, widely applied in the vulcanization of chloroprene rubber, styrene-butadiene rosin rubber, and cis-butadiene rubber. As a secondary accelerator, when used in combination with thiuram, guanidine, and thiazole accelerators, it can increase their activity, resulting in tough and resistant-aging rubber products.

[0003] While there are currently a few reports on the applications of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine, such as its use in the preparation of rubber compositions of diene elastomers in Michelin Technology's patent CN 1257212C, there are very few reports on the synthesis of this compound, both domestically and internationally. The synthesis of its analogue, 3,5-diethyl-1-phenyl-2-propyl-1,2-dihydropyridine (DHP), has also been reported only briefly. For example, the synthesis method of DHP reported in US patent US11351783 is as follows: In a 1000 mL four-necked flask equipped with a mechanical stirrer, reflux condenser, thermometer, and adding funnel, under stirring and cooling conditions, 216.3 g (3.0 mol) of butyraldehyde, 60 g (0.64 mol) of aniline, and 9.8 g (0.16 mol) of acetic acid are added to the flask. After each addition of reactants, the mixture was maintained at 20-25°C. The reaction temperature was then gradually increased to 45°C and held for one hour, followed by heating to 75°C and holding for five hours. After cooling, the reaction mixture was distilled under reduced pressure through a 14-inch packed column to obtain DHP. Gas chromatography analysis of the fraction revealed a butyraldehyde content of 9.32%, a 2-ethylhexyl-2-enal (dimolecule butyraldehyde condensate) content of 20.66%, an aniline content of 0.01%, a DHP content of 52.66%, and a DHP yield of 76%. Similarly, Chen Fangtao of Yantai University, in his master's thesis "Total Synthesis of Saframycin C and Process Study of Aldehyde-Amine Sulfation Accelerators," improved the DHP process as follows: Under nitrogen protection, aniline was slowly added to n-butyraldehyde at 0°C, followed by acetic acid. The temperature was rapidly increased to 75°C and held for 1 hour, then further increased to 100°C and reacted for another hour. Water washing and distillation yielded a DHP product with a yield of 60% and a purity of 90%. The specific synthetic reaction equation for DHP is as follows:

[0004]

[0005] In the DHP synthesis process, the product is purified by vacuum distillation in subsequent steps. This usually requires a special distillation device, and it is difficult to completely remove butyraldehyde from the product. Therefore, there is still a high content of butyraldehyde residue in the product, which affects the product's odor and use.

[0006] There are few reports on 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Although the structure of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine differs from that of DHP only in the substituents, an attempt was made to replace butyraldehyde with an equimolar amount of n-heptaldehyde according to the synthetic method reported by DHP. It was found that due to the significant difference in reactivity between n-heptaldehyde and butyraldehyde, the product obtained contained only a small amount (about 5%) of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Furthermore, the boiling point of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine is much higher than that of DHP, making it unsuitable for purification using the purification method of DHP (vacuum distillation).

[0007] Furthermore, when 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine is used in the curing of latex, it needs to have high-temperature stability to avoid decomposition and a decrease in the solid content of the product. Therefore, developing a synthetic method for highly stable 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine is of great importance to the rubber products industry. Summary of the Invention

[0008] To overcome the aforementioned technical defects in the prior art, this invention provides a method for synthesizing highly stable 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine.

[0009] To achieve the above objectives, the technical solution adopted by this invention is: a method for synthesizing highly stable 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine, the synthesis steps of which include the following:

[0010] (1) Add n-heptanol, catalyst, and water-binding agent to the reactor and stir to mix;

[0011] (2) Control the temperature, add aniline dropwise, and after the addition is complete, keep the temperature high for a certain period of time to allow the reaction to proceed;

[0012] (3) Add water to wash, let stand to separate into layers, remove the lower aqueous phase, and repeat the operation until the pH value of the lower aqueous phase is 5~7;

[0013] (4) After adding the decomposition inhibitor, the system is distilled under reduced pressure to remove the water generated in the system and recover n-heptaldehyde. The remaining liquid is the crude product.

[0014] It also includes a purification step, in which 1.5 to 3 times the mass of the crude product is added to the crude product obtained in (4), and the temperature is raised to 110 to 120°C and slowly distilled until there is no more n-heptaldehyde in the distillate. Then, the water is removed under reduced pressure at -0.098 MPa and 125 to 130°C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine with a heptanaldehyde content of <0.1%.

[0015] The synthesis equation is as follows:

[0016]

[0017] Preferably, the preparation method is characterized in that the catalyst is formic acid, acetic acid, propionic acid, or a mixture thereof, and its amount is 5% to 20% of the mass of aniline.

[0018] Preferably, the water-binding agent is a compound that can bind water molecules to form bound water, such as anhydrous sodium sulfate, anhydrous magnesium sulfate, or anhydrous calcium chloride, and its amount is 4 to 6 times the mass of aniline.

[0019] Preferably, the decomposition inhibitor refers to a weakly alkaline long-chain alkyl organic base or long-chain alkyl organic acid salt, such as sodium stearate, sodium dodecylbenzene sulfonate, dinonylamine, etc., and the amount of the decomposition inhibitor added is such that the pH value of the system is maintained at 7.0~7.10.

[0020] Preferably, the aniline is added at a temperature of 30-40°C for 5-15 hours.

[0021] Preferably, the heat preservation reaction time refers to 1 to 10 hours at 30 to 40°C.

[0022] Preferably, the molar ratio of aniline to n-heptaldehyde is 1:4~6.

[0023] Preferably, the vacuum distillation refers to reducing the pressure to below -0.098 MPa, slowly raising the temperature to 125~130℃, and holding the temperature until no more liquid evaporates.

[0024] Preferably, the product obtained by the method for synthesizing 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine has high stability, i.e., the weight loss upon heating at 100°C for 4 hours is less than 2%.

[0025] The beneficial effects achieved by this invention are as follows:

[0026] ① Through the research on the synthesis of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine by this invention, it was found that the formation stage of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine is mainly in the low-temperature range. According to the reaction mechanism, a large amount of water by-product will be generated during the reaction of n-heptaldehyde and aniline to produce 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. In this invention, a water-binding agent is added during the low-temperature reaction stage to eliminate the water by-product generated during the reaction from the system in a timely manner, thereby converting more raw materials into products more quickly.

[0027] ② After the reaction in the low-temperature section is completed, the acidic catalyst is removed in time by washing with water. Then, a decomposition inhibitor is added to maintain the pH value of the system between 7.0 and 7.10, which prevents the excess n-heptaldehyde from further self-condensing to form byproducts. At the same time, it can avoid the decomposition of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine when recovering excess n-heptaldehyde at high temperature in the later stage, so that the content of the final product is ≥70%.

[0028] ③ Because decomposition inhibitors are added to the product, it can remain neutral to slightly alkaline during subsequent storage or high temperature. Under the condition of keeping the product at 100℃ for 4 hours, the product heating loss is less than 2%, thereby improving the storage stability of the product and reducing the reduction of solid content during high temperature curing of latex.

[0029] ④ In industrial production, the negative pressure of reaction equipment can generally only reach about -0.098 MPa, while the boiling point of n-heptaldehyde is about 152℃. Below 130℃, n-heptaldehyde cannot be completely distilled off. Above 130℃, the product will quickly oxidize and change color, and even generate more acidic substances, making the product easier to decompose. Therefore, n-heptaldehyde cannot be completely removed by simple vacuum distillation. The small amount of n-heptaldehyde remaining in the product will also give the product a strong unpleasant odor.

[0030] This invention recovers most of the n-heptaldehyde by vacuum distillation, then adds a large amount of water to the reaction system and slowly distills the water out of the system. During the distillation process, the n-heptaldehyde remaining in the crude product slowly dissipates into n-heptaldehyde gas and is continuously discharged from the system along with the water vapor. This allows the n-heptaldehyde content in the product to be reduced to below 0.1% at a lower distillation temperature. Detailed Implementation

[0031] The present invention will be further described below through specific embodiments.

[0032] In this example, the high-temperature stability of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine was characterized by the weight loss upon heating at 100℃ for 4 hours. The specific detection method was as follows:

[0033] 1. Weigh out an open petri dish with a diameter of 10 cm, and let its mass be m1;

[0034] 2. Weigh 4.9~5.1g of sample into a petri dish and record the sample mass as m2;

[0035] 3. Place the petri dishes in a 100℃ oven for 4 hours;

[0036] 4. Weigh the total mass of the culture dish and sample after incubation, which is m3;

[0037]

[0038] Example 1

[0039] In this embodiment, the molar ratio of n-heptaldehyde to aniline is 6:1, the formic acid (catalyst) is 5% of the mass of aniline, the decomposition inhibitor is sodium dodecylbenzenesulfonate, and the water-binding agent is anhydrous sodium sulfate, which is used in an amount of 6 times the mass of aniline.

[0040] Add 224.08 g of n-heptanal (98% by mass), 1.50 g of formic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and stirred. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to a 1 In a 000 mL negative pressure distillation apparatus, sodium dodecylbenzenesulfonate was added to adjust the pH of the system to approximately 7.06. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then removed under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 72.60%, the weight loss after heating at 100 °C for 4 hours was 1.89%, and the n-heptaldehyde content was 0.06%.

[0041] Example 2

[0042] This embodiment is based on Example 1, with the molar ratio of n-heptaldehyde to aniline adjusted to 5:1, while keeping other conditions unchanged.

[0043] Add 186.74 g of n-heptanal (98% by mass), 1.50 g of formic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and stirred. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to a 1 In a 000 mL negative pressure distillation apparatus, sodium dodecylbenzenesulfonate was added to adjust the pH of the system to approximately 7.06. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then removed under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 75.30%, the weight loss after heating at 100 °C for 4 hours was 1.64%, and the n-heptaldehyde content was 0.05%.

[0044] The results above show that adjusting the molar ratio of n-heptaldehyde to aniline to 5:1 increases the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine and reduces the weight loss upon heating. This is because less n-heptaldehyde remains in the system after the low-temperature reaction, resulting in fewer side reactions and fewer byproducts during subsequent n-heptaldehyde recovery.

[0045] Example 3

[0046] This embodiment is based on Example 1, with the molar ratio of n-heptaldehyde to aniline adjusted to 4:1, while keeping other conditions unchanged.

[0047] Add 149.39 g of n-heptanal (98% by mass), 1.50 g of formic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to a 1 In a 000 mL negative pressure distillation apparatus, sodium dodecylbenzenesulfonate was added to adjust the pH of the system to approximately 7.06. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then removed under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 70.58%, the weight loss upon heating at 100 °C for 4 hours was 1.95%, and the n-heptaldehyde content was 0.03%.

[0048] The results above show that further reducing the amount of n-heptanal and adjusting the molar ratio of n-heptanal to aniline to 4:1 reduces the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine and increases the weight loss upon heating. This is because the reduced amount of n-heptanal leads to less formation of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine at low temperatures, while increasing the formation of byproducts.

[0049] Example 4

[0050] This embodiment is based on Example 2, except that the catalyst formic acid is replaced with acetic acid while keeping the amount the same, and all other conditions remain unchanged.

[0051] Add 186.74 g of n-heptanal (98% by mass), 1.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to a 1 In a 000 mL negative pressure distillation apparatus, sodium dodecylbenzenesulfonate was added to adjust the pH of the system to approximately 7.06. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then removed under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 71.10%, the weight loss after heating at 100 °C for 4 hours was 1.91%, and the n-heptaldehyde content was 0.06%.

[0052] The results above show that replacing formic acid with acetic acid as the catalyst reduces the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine and increases the weight loss upon heating. This is because acetic acid is less acidic than formic acid, resulting in less formation of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine and more formation of byproducts.

[0053] Example 5

[0054] This embodiment is based on Example 4, with the amount of acetic acid catalyst increased to 15% of the amount of aniline, while keeping other conditions unchanged.

[0055] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and stirred. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to a 1 In a 000 mL negative pressure distillation apparatus, sodium dodecylbenzenesulfonate was added to adjust the pH of the system to approximately 7.06. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then removed under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 77.28%, the weight loss after heating at 100 °C for 4 hours was 1.15%, and the n-heptaldehyde content was 0.04%.

[0056] The results above show that increasing the amount of acetic acid as a catalyst to 15% significantly increases the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine and greatly reduces the weight loss upon heating. This is because increasing the amount of acetic acid enhances the catalytic effect, resulting in the formation of more 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine and a reduction in the formation of byproducts.

[0057] Example 6

[0058] This embodiment is based on Example 4, except that the catalyst formic acid is replaced with propionic acid and the amount is adjusted to 20% of the mass of aniline, while other conditions remain unchanged.

[0059] Add 186.74 g of n-heptanal (98% by mass), 6.00 g of propionic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to a 1 In a 000 mL negative pressure distillation apparatus, sodium dodecylbenzenesulfonate was added to adjust the pH of the system to approximately 7.06. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then removed under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 71.53%, the weight loss after heating at 100 °C for 4 hours was 1.93%, and the n-heptaldehyde content was 0.07%.

[0060] The results above show that even though the amount of acetic acid used as the catalyst was increased to 20% by replacing it with formic acid, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine in the product only increased slightly, and the reduction in catalytic activity upon heating was minimal. This is because propionic acid is a weaker acid, and although the amount used was increased, the catalytic effect was not significantly enhanced.

[0061] Example 7

[0062] This embodiment is based on Example 5, except that the decomposition inhibitor is replaced with sodium stearate, while all other conditions remain unchanged.

[0063] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to... The solution was placed in a 1000 mL negative pressure distillation apparatus, and sodium stearate was added to adjust the pH of the system to approximately 7.06. The water circulation vacuum pump was turned on, and the system pressure was lowered to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, and 250 mL of water was added. The temperature was then slowly increased to 110–120 °C, and the solution was slowly distilled until no more n-heptaldehyde was present in the distillate. The solution was then dehydrated under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 77.29%, the weight loss after heating at 100 °C for 4 hours was 0.98%, and the n-heptaldehyde content was 0.04%.

[0064] The results above show that replacing the decomposition inhibitor with sodium stearate did not significantly change the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine, although the weight loss upon heating decreased. This is likely because sodium stearate is less basic, requiring a larger amount to adjust to the same pH value. Therefore, it can more quickly consume the generated acidic substances during subsequent high-temperature distillation, improving product stability.

[0065] Example 8

[0066] This embodiment is based on Example 7, with the addition of sodium stearate as a decomposition inhibitor, and the pH value of the system before distillation is increased to approximately 7.10, while keeping other conditions unchanged.

[0067] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 15 hours. Continue to maintain the temperature at 30-40°C for 1 hour. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to... The mixture was placed in a 1000 mL negative pressure distillation apparatus, and sodium stearate was added to adjust the pH of the system to approximately 7.10. The water circulation vacuum pump was turned on, and the system pressure was lowered to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, and 250 mL of water was added. The temperature was then slowly increased to 110–120 °C, and the mixture was slowly distilled until no more n-heptaldehyde was present in the distillate. The mixture was then dehydrated under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 77.31%, the weight loss upon heating at 100 °C for 4 hours was 0.86%, and the n-heptaldehyde content was 0.05%.

[0068] The results above show that increasing the amount of sodium stearate, a decomposition inhibitor, slightly increased the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine, while further reducing the weight loss upon heating. This indicates that the product stability was further improved during subsequent high-temperature distillation, resulting in less product decomposition and thus a higher product content.

[0069] Example 9

[0070] This embodiment was carried out based on Example 8, with the aniline dropping time adjusted to 5 hours and the heat preservation time after dropping to 10 hours, while keeping other conditions unchanged.

[0071] 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) were added to a 1000 ml flask. The mixture was stirred and the temperature was controlled at 30-40°C. 30.00 g of aniline (99.5% by mass) was slowly added dropwise over approximately 5 hours. The mixture was then kept at 30-40°C for another 10 hours. Water was added until the mixture was completely dissolved. The reaction solution was then transferred to a pear-shaped separatory funnel. After allowing the layers to separate, the lower aqueous phase was removed. The mixture was then washed with water in the pear-shaped separatory funnel until the pH reached 5-7. The reaction solution was then transferred to… The solution was placed in a 1000 mL negative pressure distillation apparatus, and sodium stearate was added to adjust the pH of the system to approximately 7.10. The water circulation vacuum pump was turned on, and the system pressure was lowered to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then dehydrated under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 73.01%, the weight loss after heating at 100 °C for 4 hours was 1.85%, and the n-heptaldehyde content was 0.05%.

[0072] The results above show that when the aniline dropping time was reduced to 5 h and the holding time was extended to 10 h, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine decreased to 73.01%, and the heating loss increased to 1.85%.

[0073] Example 10

[0074] This embodiment was carried out based on Example 8, with the aniline dropping time adjusted to 10 hours and the heat preservation time after dropping to 4 hours, while keeping other conditions unchanged.

[0075] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 10 hours. Continue to maintain the temperature at 30-40°C for 4 hours. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to... The solution was placed in a 1000 mL negative pressure distillation apparatus, and sodium stearate was added to adjust the pH of the system to approximately 7.10. The water circulation vacuum pump was turned on, and the system pressure was lowered to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, 250 mL of water was added, and the temperature was slowly increased to 110–120 °C. Distillation continued until no more n-heptaldehyde was present in the distillate. The solution was then dehydrated under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 77.89%, the weight loss after heating at 100 °C for 4 hours was 0.82%, and the n-heptaldehyde content was 0.04%.

[0076] The results above show that when the aniline addition time is reduced to 10 h and the holding time is extended to 4 h, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine increases slightly and the heating loss decreases slightly.

[0077] Example 11

[0078] This embodiment is based on Example 10, with the decomposition inhibitor sodium stearate replaced by dinonylamine, while keeping everything else unchanged.

[0079] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 10 hours. Continue to maintain the temperature at 30-40°C for 4 hours. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to... The solution was placed in a 1000 mL negative pressure distillation apparatus, and dinonylamine was added to adjust the pH of the system to approximately 7.10. The water circulation vacuum pump was turned on, and the system pressure was lowered to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, and 250 mL of water was added. The temperature was then slowly increased to 110–120 °C, and the solution was slowly distilled until no more n-heptaldehyde was present in the distillate. The solution was then dehydrated under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 75.73%, the weight loss after heating at 100 °C for 4 hours was 1.69%, and the n-heptaldehyde content was 0.05%.

[0080] The results above show that after adjusting the decomposition inhibitor sodium stearate to dinonylamine, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine decreased to 75.73%, and the weight loss upon heating increased to 1.69%.

[0081] Example 12

[0082] This embodiment was carried out based on Example 10, with the amount of anhydrous sodium sulfate as the water-binding agent adjusted to 4 times the mass of aniline, while keeping other conditions unchanged.

[0083] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 120.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 10 hours. Continue to maintain the temperature at 30-40°C for 4 hours. Add water until the solution is clear and dissolved. Transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH reaches 5-7. Transfer the reaction solution to... The mixture was placed in a 1000 mL negative pressure distillation apparatus, and sodium stearate was added to adjust the pH of the system to approximately 7.10. The water circulation vacuum pump was turned on, and the system pressure was lowered to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure, and 250 mL of water was added. The temperature was then slowly increased to 110–120 °C, and the mixture was slowly distilled until no more n-heptaldehyde was present in the distillate. The mixture was then dehydrated under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 72.22%, the weight loss after heating at 100 °C for 4 hours was 1.90%, and the n-heptaldehyde content was 0.04%.

[0084] The results above show that after reducing the amount of anhydrous ammonium sulfate as a water-binding agent, the water-binding effect weakens, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine decreases to 72.22%, and the weight loss upon heating increases to 1.90%.

[0085] Comparative Example 1

[0086] This comparative example was conducted based on Example 10, except that the water-binding agent was removed, while all other conditions remained unchanged.

[0087] Add 186.74 g of n-heptanal (98% by mass) and 4.50 g of acetic acid (99% by mass) to a 1000 mL flask, stir and control the temperature at 30-40 °C, slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 10 hours, and continue to maintain the temperature at 30-40 °C for 4 hours; add water until the solution is clear, transfer the reaction solution to a pear-shaped separatory funnel, allow it to stand and separate into layers, remove the lower aqueous phase, and continue washing with water in the pear-shaped separatory funnel until the pH value is 5-7; transfer the reaction solution to a 1000 mL negative pressure distillation tank. In the apparatus, sodium stearate was added to adjust the pH of the system to approximately 7.10. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and maintained until no more liquid evaporated. The inlet valve was opened to release the negative pressure, and 250 mL of water was added. The temperature was then slowly increased to 110–120 °C, and the distillate was slowly distilled until no more n-heptaldehyde was present in the distillate. The solution was then removed under reduced pressure at -0.098 MPa and 125–130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 66.32%, the weight loss after heating at 100 °C for 4 hours was 2.36%, and the n-heptaldehyde content was 0.05%.

[0088] The results above show that without the addition of a water-binding agent, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine decreased to 66.32%, and the weight loss upon heating increased to 2.36%.

[0089] Comparative Example 2

[0090] This comparative example was conducted based on Example 10, except that the use of the decomposition inhibitor was removed, while all other conditions remained unchanged.

[0091] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 10 hours. Continue to maintain the temperature at 30-40°C for 4 hours. Add water until the solution is clear and dissolved. Transfer the reaction mixture to a pear-shaped separatory funnel. After allowing it to separate into layers, remove the lower aqueous phase. Continue washing with water in the pear-shaped separatory funnel until the pH value is reached. The reaction mixture was transferred to a 1000 mL negative pressure distillation apparatus. A water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly raised to 125-130 °C and maintained until no more liquid distilled off. The inlet valve was opened to release the negative pressure. 250 mL of water was added, and the temperature was slowly raised to 110-120 °C. Distillation was continued until no more n-heptaldehyde was present in the distillate. The mixture was then dehydrated under reduced pressure at -0.098 MPa and 125-130 °C to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 68.94%, the weight loss upon heating at 100 °C for 4 hours was 3.54%, and the n-heptaldehyde content was 0.06%.

[0092] The results above show that without the addition of decomposition inhibitors, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine decreased to 68.94%, and the weight loss upon heating increased to 3.54%.

[0093] Comparative Example 3

[0094] This embodiment is based on Example 10, except that the water distillation and subsequent dehydration steps in the post-treatment are removed, while all other conditions remain unchanged.

[0095] Add 186.74 g of n-heptanal (98% by mass), 4.50 g of acetic acid (99% by mass), and 180.00 g of anhydrous sodium sulfate (99% by mass) to a 1000 ml flask. Stir and control the temperature at 30-40°C. Slowly add 30.00 g of aniline (99.5% by mass) dropwise over approximately 10 hours. Continue to maintain the temperature at 30-40°C for 4 hours. Add water until the solution is completely dissolved. Transfer the reaction mixture to a pear-shaped separatory funnel. After standing and separating the layers, the lower aqueous phase was removed, and the mixture was washed with water in a pear-shaped separatory funnel until the pH reached 5-7. The reaction solution was transferred to a 1000 mL negative pressure distillation apparatus, and sodium stearate was added to adjust the pH to approximately 7.10. The water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125-130 °C and maintained until no more liquid distilled off, yielding 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis showed that the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine content was 72.49%, the weight loss upon heating at 100 °C for 4 h was 4.56%, and the n-heptanal content was 5.31%.

[0096] The results above show that after removing the water distillation and subsequent dehydration steps in the post-treatment, the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine decreased to 72.49% due to the large amount of n-heptaldehyde residue, and the weight loss upon heating increased to 4.56%.

[0097] Comparative Example 4

[0098] This comparative example follows the DHP synthesis method described in Chen Fangtao's master's thesis "Total Synthesis of Saframycin C and Process Study of Aldehyde-Amine Sulfation Accelerators" at Yantai University, except that butyraldehyde was replaced with an equimolar proportion of n-heptaldehyde.

[0099] 186.74 g of n-heptanal (98% by mass) was added to a 1000 mL flask and cooled to 0 °C. After purging the system with nitrogen, nitrogen was continuously introduced, and 30.00 g of aniline (99.5% by mass) was slowly added dropwise, followed by 4.50 g of acetic acid (99% by mass). The temperature was rapidly increased to 75 °C and held for 1 hour. The temperature was then increased to 100 °C and reacted for another hour. The mixture was cooled to below 30 °C, the nitrogen was removed, and the mixture was washed with water until the pH was approximately 5–7. The reaction solution was transferred to a 1000 mL negative pressure distillation apparatus. A water circulation vacuum pump was turned on, and the system pressure was reduced to -0.098 MPa. The temperature was then slowly increased to 125–130 °C and held until no more liquid was distilled off to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine. Gas chromatography analysis revealed that the content of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine was 4.89%, the weight loss upon heating at 100℃ for 4 hours was 12.58%, and the content of n-heptanal was 10.69%.

[0100] The results above show that the synthesis of 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine according to the DHP synthesis method in the literature yielded a content of only 4.89%, a heating loss of 12.58%, and a heptanal residue of 10.69%.

[0101] The above specific embodiments are used to explain and illustrate the present invention, but not to limit the present invention. Any modifications and changes made to the present invention within the spirit and scope of the claims shall fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine, characterized in that... Its synthesis steps include the following: (1) Add n-heptanol, catalyst, and water-binding agent to the reactor and stir to mix; (2) Control the temperature, add aniline dropwise, and after the addition is complete, maintain the temperature for the reaction; (3) Add water to wash, let stand to separate into layers, remove the lower aqueous phase, and repeat the operation until the pH value of the lower aqueous phase is 5~7; (4) After adding the decomposition inhibitor, the sample was distilled under reduced pressure to obtain 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine; The catalyst is formic acid, acetic acid, propionic acid, or a mixture thereof.

2. The preparation method according to claim 1, characterized in that, The process also includes a purification step, in which 1.5 to 3 times the mass of water is added to the 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine obtained in (4), and the mixture is heated to 110 to 120°C and slowly distilled until there is no more n-heptaldehyde in the distillate. Then, the mixture is dehydrated under reduced pressure at -0.098 MPa and 125 to 130°C to obtain high-quality 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine with a heptanaldehyde content of <0.1%.

3. The preparation method according to claim 1, characterized in that, The amount of catalyst used is 5% to 20% of the mass of aniline; The water-binding agent is a compound that can bind water molecules to form bound water, and its amount is 4 to 6 times the mass of aniline.

4. The preparation method according to claim 3, characterized in that, The decomposition inhibitor refers to a weakly alkaline long-chain alkyl organic base or long-chain alkyl organic acid salt, and the amount of the decomposition inhibitor added is such that the pH of the system is maintained at 7.0~7.

10.

5. The preparation method according to claim 4, characterized in that, The water-binding agent is anhydrous sodium sulfate, anhydrous magnesium sulfate or anhydrous calcium chloride, and the decomposition inhibitor is sodium stearate, sodium dodecylbenzenesulfonate or dinonylamine; the temperature at which aniline is added in step (2) is 30~40℃ and the time for adding it is 5~15h.

6. The preparation method according to claim 1, characterized in that, The heat preservation reaction refers to a heat preservation reaction at 30~40℃ for 1~10 hours.

7. The preparation method according to claim 1, characterized in that, The molar ratio of aniline to n-heptaldehyde is 1:4~6.

8. The preparation method according to claim 1, characterized in that, The product obtained by the method for synthesizing 3,5-dipentyl-2-hexyl-1-phenyl-1,2-dihydropyridine has high stability, i.e., the weight loss upon heating at 100℃ for 4 hours is <2%.

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