A kind of synthetic method of 5-ethyl-2-pyridineethanol

Abstract

The present invention discloses a method for synthesizing 5-ethyl-2-pyridineethanol, belonging to the technical field of organic synthesis. The present invention provides a method for synthesizing 5-ethyl-2-pyridineethanol. The method uses a specially prepared solid acid catalyst as a catalyst, paraldehyde and ammonia as raw materials, and adjusts the amounts of the raw materials and catalyst, vaporization temperature, reaction temperature, and reaction pressure. The yield of 2-methyl-5-ethylpyridine is as high as 86.5%. The obtained 2-methyl-5-ethylpyridine is reacted with a 37% methanol aqueous solution by adjusting the reaction conditions. The total yield of the final product, 5-ethyl-2-pyridineethanol, is as high as 81.2%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 5-ethyl-2-pyridineethanol. Background Art

[0002] Pioglitazone hydrochloride is a new type of insulin sensitizer with a good therapeutic effect in the treatment of non-insulin-dependent diabetes mellitus. 5-ethyl-2-pyridineethanol is an important intermediate in the synthesis of this drug, and research on its synthesis process is of great significance.

[0003] 5-Ethyl-2-pyridineethanol is synthesized in two steps. First, acetaldehyde or paraldehyde reacts with aqueous ammonia to form the intermediate 2-methyl-5-ethylpyridine. Then, 2-methyl-5-ethylpyridine reacts with aqueous formaldehyde to produce the target product. The synthesis process for both substances significantly impacts the quality and yield of the final product.

[0004] 5-ethyl-2-pyridineethanol and the key intermediate 2-methyl-5-ethylpyridine for synthesizing it are important organic intermediates widely used in the chemical and pharmaceutical industries, and are in great demand at home. However, the production capacity of my country to this class of products is relatively weak at present, and relevant research is not deep enough, and technology cannot reach international level, and does not form large-scale production. Along with the research and development efforts of my country's fine chemical products, the consumption of these two pyridine derivatives is constantly increased, but the main source is still import, and the domestic production scale is small. Strengthening the research and development of this product and building large-scale production equipment will effectively alleviate the dependence of my country's pyridine series products on imports and promote the research and development of downstream products. Therefore, the synthesis process research of 5-ethyl-2-pyridineethanol and its intermediates has important economic and social benefits.

[0005] However, current synthesis processes mostly use liquid phase synthesis, which generally has problems such as low raw material utilization, many by-products, difficult product separation, and low product yield. Compared with the liquid phase method, the gas phase method has fewer by-products, easy product separation, and low reaction pressure, which is much lower than the liquid phase method, greatly reducing costs. However, the gas phase method is not yet mature enough for the synthesis of 5-ethyl-2-pyridineethanol, resulting in a low product yield.

[0006] Based on this, we proposed a method for synthesizing 5-ethyl-2-pyridineethanol, hoping to solve the shortcomings of the existing technology. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for synthesizing 5-ethyl-2-pyridineethanol in response to the existing problems.

[0008] The present invention is achieved through the following technical solutions:

[0009] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0010] S1. A solid acid catalyst is placed in a reactor continuously flowing with nitrogen, the reactor and vaporizer are heated to a specified temperature, and then paraldehyde and ammonia are added together into the vaporizer for vaporization. After vaporization, the mixture enters the reactor for reaction. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is subjected to vacuum distillation to collect a fraction at 60-100° C., which is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0011] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 90-100°C, add 37% formaldehyde solution, heat it to 160°C, maintain it for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to evaporate the unreacted formaldehyde and the water therein under reduced pressure, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0012] Preferably, the mass ratio of paraldehyde, aqueous ammonia and solid catalyst in step S1 is 1:3-4:0.2-1.2.

[0013] Preferably, the temperature of the vaporizer in step S1 is 160-180°C;

[0014] The temperature of the reactor is 175-235°C;

[0015] The reaction pressure is controlled at 0.2-0.4 MPa.

[0016] Preferably, the preparation of the solid acid catalyst in step S1 comprises the following steps:

[0017] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.2-0.3 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 7-11% of the mixed solution, and then ammonia water was added dropwise while stirring until the pH of the system was 9-10 to obtain Ce(OH)4-Al(OH)3 precipitate, aged for 6-7 hours, filtered, washed with deionized water 2-4 times, and dried at 70-80°C to obtain a Ce(OH)4-Al(OH)3 composite support;

[0018] (2) The Ce(OH)4-Al(OH)3 composite carrier was subjected to ultrasonic-magnetic field coupling treatment, and then immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio of 1:8-16. After immersion for 30-50 minutes, it was filtered and placed in a vacuum drying oven for low-temperature vacuum drying, and then calcined to obtain SO4 2- / (CeO2-Al2O3);

[0019] (3) Ultrasonic dispersion of nano-silica in 50% ethanol solution, then adding dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 30-40°C, 200-300 rpm for 12-16 h, centrifuging at 8000-10000 rpm for 10-15 min, washing the precipitate with deionized water 3-5 times, and drying at 50-60°C to constant weight to obtain pre-modified nano-silica, adding the solution to a reactor, adding toluene solution for ultrasonic dispersion, heating to 70-80°C, adding 0.7-1 times the mass of the precipitate with thionyl chloride, stirring at 300-400 rpm, 80-90°C for 40-50 min, filtering, washing with deionized water 3-5 times, and drying at 40-50°C under vacuum for 10-12 h to obtain modified nano-silica;

[0020] (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica are added into a bead mill in a mass ratio of 20-30:1, and ground at 500-1000 rpm for 20-30 minutes to obtain a solid acid catalyst.

[0021] Preferably, the ingredients and corresponding weight percentages of the auxiliary agent in step (1) are: 2-3% hydroxypropyl methylcellulose, 2-3% polyvinyl alcohol, 5-9% soy lecithin, and the balance is deionized water.

[0022] Preferably, the ultrasonic power in step (2) is 50-150W, the ultrasonic frequency is 20kHz, the DC magnetic field power is 1000-1500W, and the treatment time is 2-3min;

[0023] During the low-temperature vacuum drying process, the vacuum degree is controlled to be 10-20 Pa and the temperature is 20-40° C.

[0024] The calcination temperature is 500-600°C.

[0025] Preferably, the mass volume ratio of the nano-silica to 50% ethanol in step (3) is 1 g: 90-140 mL;

[0026] The amount of dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride added is 4-8% of the total volume of 50% ethanol;

[0027] The mass ratio of the pre-modified nano-silica to toluene is 1:300-400.

[0028] Preferably, the reaction process of step S1 is:

[0029]

[0030] Preferably, the mass ratio of the 5-ethyl-2-pyridineethanol intermediate I described in step S2 to the 37% formaldehyde solution is 1:0.3-0.6.

[0031] Preferably, the reaction process of step S2 is:

[0032]

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] The invention provides a method for synthesizing 5-ethyl-2-pyridineethanol. The method comprises the following steps: using a specially prepared solid acid catalyst as a catalyst, using paraldehyde and ammonia as raw materials, adjusting the amounts of the raw materials and the catalyst, the vaporization temperature, the reaction temperature and the reaction pressure, and finally achieving a yield of 2-methyl-5-ethylpyridine as high as 86.5%. The obtained 2-methyl-5-ethylpyridine is reacted with a 37% methanol aqueous solution by adjusting the reaction conditions, and finally achieving a total yield of 5-ethyl-2-pyridineethanol as a final product as high as 81.2%.

[0035] First, under the action of an additive and a precipitant, a 5-ethyl-2-pyridineethanol composite carrier is coprecipitated. The presence of the additive creates a steric hindrance effect, preventing precipitate agglomeration, changing the particle stacking properties, and increasing the pore volume after subsequent calcination, thereby increasing the carrier's specific surface area. Ultrasonic-DC magnetic field coupling treatment and low-temperature vacuum drying work together to change the carrier's microporous structure, increase porosity, and improve the selectivity of the solid acid catalyst and the conversion rate of the product. Nano-silica is modified with dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride and thionyl chloride to exhibit high surface properties, stability, and dispersibility. The modified nano-silica is then added to further improve the catalytic activity and stability of the catalyst.

[0036] The solid acid catalyst is used in the synthesis of 5-ethyl-2-pyridineethanol intermediate I, and has significant catalytic activity, thereby improving the yield of 5-ethyl-2-pyridineethanol intermediate I. In addition, the catalyst has high stability and can be recycled and reused, thereby greatly reducing production costs.

[0037] Secondly, when the 5-ethyl-2-pyridineethanol intermediate I obtained by the present invention is used as a raw material in the step, the unreacted 5-ethyl-2-pyridineethanol intermediate I can be recovered and reused. The recycling method greatly improves the utilization rate of the raw material 2-methyl-5-ethylpyridine, making this method for preparing 5-ethyl-2-pyridineethanol have greater advantages.

[0038] Finally, the present invention not only provides a method for synthesizing 5-ethyl-2-pyridineethanol and its intermediates, but also provides a catalyst with high activity, high selectivity and high stability for the chemical industry. DETAILED DESCRIPTION

[0039] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0040] Example 1

[0041] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0042] S1. The solid acid catalyst is loaded into a reactor continuously purged with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 160° C., and the vaporized product enters the reactor for reaction at 175° C. and 0.2 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The 60-100° C. fraction is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0043] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:3:0.2;

[0044] The preparation of the solid acid catalyst comprises the following steps:

[0045] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.2 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 7% of the mixed solution. Ammonia water was then added dropwise while stirring until the pH of the system reached 9 to obtain a Ce(OH)4-Al(OH)3 precipitate. After aging for 6 h, the precipitate was filtered, washed twice with deionized water, and dried at 70-80°C to obtain a Ce(OH)4-Al(OH)3 composite support.

[0046] The ingredients and corresponding weight percentages of the auxiliary agent are: 2% hydroxypropyl methylcellulose, 2% polyvinyl alcohol, 5% soy lecithin, and the balance is deionized water;

[0047] (2) The Ce(OH)4-Al(OH)3 composite carrier was subjected to ultrasonic-magnetic field coupling treatment, with the ultrasonic power controlled at 50W, the ultrasonic frequency at 20kHz, and the DC magnetic field power at 1000W. After treatment for 2 minutes, it was immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio controlled at 1:8. After immersion for 30 minutes, it was filtered and placed in a vacuum drying oven at 10Pa and 20℃ for low-temperature vacuum drying. It was then calcined at 500℃ to obtain SO4 2- / (CeO2-Al2O3);

[0048] (3) Ultrasonic dispersion of nano-silica in a 50% ethanol solution, with a mass volume ratio of nano-silica to 50% ethanol of 1 g:90 mL, followed by addition of 4% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 30°C and 200 rpm for 12 h, centrifuging at 8000 rpm for 10 min, washing the precipitate three times with deionized water, and drying at 50°C to constant weight to obtain pre-modified nano-silica, which was added to a reactor, and a 300-fold toluene solution of the pre-modified nano-silica was added for ultrasonic dispersion, then heated to 70°C, and 0.7-fold thionyl chloride of the precipitate mass was added, stirring at 300 rpm and 80°C for 40 min, then filtered, washed three times with deionized water, and dried at 40°C under vacuum for 10 h to obtain modified nano-silica;

[0049] (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica were added into a bead mill at a mass ratio of 20:1 and ground at 500 rpm for 20 min to obtain a solid acid catalyst;

[0050] The reaction process of step S1 is:

[0051]

[0052] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 90°C, add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.3, heat it to 160°C, maintain for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it, first use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0053] The reaction process of step S2 is:

[0054]

[0055] Example 2

[0056] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0057] S1. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C. After vaporization, the mixture enters the reactor for reaction at 205°C and 0.3 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The fraction at 60-100°C is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0058] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:3.5:0.7;

[0059] The preparation of the solid acid catalyst comprises the following steps:

[0060] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.25 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 9% of the total volume of the mixed solution. Ammonia water was then added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate. After aging for 6.5 h, the precipitate was filtered, washed with deionized water three times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite support.

[0061] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soy lecithin, and the balance is deionized water;

[0062] (2) The Ce(OH)4-Al(OH)3 composite carrier was subjected to ultrasonic-magnetic field coupling treatment, with the ultrasonic power controlled at 100W, the ultrasonic frequency at 20kHz, and the DC magnetic field power at 1200W. After treatment for 2.5 minutes, it was immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio controlled at 1:12. After immersion for 40 minutes, it was filtered and placed in a vacuum drying oven at 15Pa and 30℃ for low-temperature vacuum drying, and then calcined at 550℃ to obtain SO4 2- / (CeO2-Al2O3);

[0063] (3) Ultrasonic dispersion of nano-silica into a 50% ethanol solution, with a mass volume ratio of nano-silica to 50% ethanol of 1 g:110 mL, followed by addition of 6% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 35°C and 250 rpm for 14 h, centrifuging at 9000 rpm for 12 min, washing the precipitate four times with deionized water, and drying at 55°C to constant weight to obtain pre-modified nano-silica, which was added to a reactor, and a 350-fold toluene solution of the pre-modified nano-silica was added for ultrasonic dispersion, then heated to 75°C, and 0.8 times the mass of the precipitate of thionyl chloride was added, stirring at 350 rpm and 85°C for 45 min, then filtered, washed four times with deionized water, and dried at 45°C under vacuum for 11 h to obtain modified nano-silica;

[0064] (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica were added into a bead mill at a mass ratio of 25:1 and ground at 700 rpm for 25 min to obtain a solid acid catalyst;

[0065] The reaction process of step S1 is:

[0066]

[0067] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 95° C., add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.45, heat it to 160° C., maintain for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0068] The reaction process of step S2 is:

[0069]

[0070] Example 3

[0071] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0072] S1. The solid acid catalyst is loaded into a reactor continuously purged with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 180° C., and the vaporized product enters the reactor for reaction at 235° C. and 0.4 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The fraction at 60-100° C. is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0073] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:4:1.2;

[0074] The preparation of the solid acid catalyst comprises the following steps:

[0075] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.3 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 11% of the mixed solution. Ammonia water was then added dropwise while stirring until the pH of the system was 10 to obtain a Ce(OH)4-Al(OH)3 precipitate. After aging for 7 h, the precipitate was filtered, washed with deionized water 4 times, and dried at 80°C to obtain a Ce(OH)4-Al(OH)3 composite support.

[0076] The ingredients and corresponding weight percentages of the auxiliary agent are: 3% hydroxypropyl methylcellulose, 3% polyvinyl alcohol, 9% soy lecithin, and the balance is deionized water;

[0077] (2) The Ce(OH)4-Al(OH)3 composite carrier was subjected to ultrasonic-magnetic field coupling treatment, with the ultrasonic power controlled at 150W, the ultrasonic frequency at 20kHz, and the DC magnetic field power at 1500W. After treatment for 3 minutes, it was immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio controlled at 1:16. After immersion for 50 minutes, it was filtered and placed in a vacuum drying oven at 20Pa and 40℃ for low-temperature vacuum drying. It was then calcined at 600℃ to obtain SO4 2- / (CeO2-Al2O3);

[0078] (3) Ultrasonic dispersion of nano-silica in a 50% ethanol solution, with a mass volume ratio of nano-silica to 50% ethanol of 1 g:140 mL, followed by addition of 8% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 40°C and 300 rpm for 16 h, centrifuging at 10,000 rpm for 15 min, washing the precipitate 5 times with deionized water, and drying at 60°C to constant weight to obtain pre-modified nano-silica, adding the solution to a reactor, adding a 400-fold toluene solution of the pre-modified nano-silica to the solution, ultrasonically dispersing the solution uniformly, heating the solution to 80°C, adding 1-fold thionyl chloride in a mass of the precipitate, stirring at 400 rpm and 90°C for 50 min, filtering the solution, washing the solution 5 times with deionized water, and drying the solution at 50°C under vacuum for 12 h to obtain modified nano-silica;

[0079] (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica were added into a bead mill at a mass ratio of 30:1 and ground at 1000 rpm for 30 min to obtain a solid acid catalyst;

[0080] The reaction process of step S1 is:

[0081]

[0082] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 100°C, add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.6, heat it to 160°C, maintain for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0083] The reaction process of step S2 is:

[0084]

[0085] Comparative Example 1

[0086] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0087] S1. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C. After vaporization, the mixture enters the reactor for reaction at 205°C and 0.3 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The fraction at 60-100°C is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0088] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:3.5:0.7;

[0089] The preparation of the solid acid catalyst comprises the following steps:

[0090] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.25 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 9% of the total volume of the mixed solution. Ammonia water was then added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate. After aging for 6.5 h, the precipitate was filtered, washed with deionized water three times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite support.

[0091] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soy lecithin, and the balance is deionized water;

[0092] (2) The Ce(OH)4-Al(OH)3 composite support was immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio of 1:12. After immersion for 40 minutes, it was filtered and placed in a vacuum drying oven at 15Pa and 30℃ for low-temperature vacuum drying. It was then calcined at 550℃ to obtain SO4 2- / (CeO2-Al2O3);

[0093] (3) Ultrasonic dispersion of nano-silica into a 50% ethanol solution, with a mass volume ratio of nano-silica to 50% ethanol of 1 g:110 mL, followed by addition of 6% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 35°C and 250 rpm for 14 h, centrifuging at 9000 rpm for 12 min, washing the precipitate four times with deionized water, and drying at 55°C to constant weight to obtain pre-modified nano-silica, which was added to a reactor, and a 350-fold toluene solution of the pre-modified nano-silica was added for ultrasonic dispersion, then heated to 75°C, and 0.8 times the mass of the precipitate of thionyl chloride was added, stirring at 350 rpm and 85°C for 45 min, then filtered, washed four times with deionized water, and dried at 45°C under vacuum for 11 h to obtain modified nano-silica;

[0094] (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica were added into a bead mill at a mass ratio of 25:1 and ground at 700 rpm for 25 min to obtain a solid acid catalyst;

[0095] The reaction process of step S1 is:

[0096]

[0097] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 95° C., add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.45, heat it to 160° C., maintain for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0098] The reaction process of step S2 is:

[0099]

[0100] Comparative Example 2

[0101] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0102] S1. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C. After vaporization, the mixture enters the reactor for reaction at 205°C and 0.3 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The fraction at 60-100°C is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0103] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:3.5:0.7;

[0104] The preparation of the solid acid catalyst comprises the following steps:

[0105] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.25 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 9% of the total volume of the mixed solution. Ammonia water was then added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate. After aging for 6.5 h, the precipitate was filtered, washed with deionized water three times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite support.

[0106] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soy lecithin, and the balance is deionized water;

[0107] (2) The Ce(OH)4-Al(OH)3 composite carrier was subjected to ultrasonic-magnetic field coupling treatment, with the ultrasonic power controlled at 100W, the ultrasonic frequency at 20kHz, and the DC magnetic field power at 1200W. After treatment for 2.5 minutes, it was immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio controlled at 1:12. After immersion for 40 minutes, it was filtered and placed in a vacuum drying oven at 15Pa and 30℃ for low-temperature vacuum drying, and then calcined at 550℃ to obtain SO4 2- / (CeO2-Al2O3);

[0108] (3) SO4 2- / (CeO2-Al2O3) and nano-silica were added into a bead mill at a mass ratio of 25:1 and ground at 700 rpm for 25 min to obtain a solid acid catalyst;

[0109] The reaction process of step S1 is:

[0110]

[0111] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 95° C., add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.45, heat it to 160° C., maintain for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0112] The reaction process of step S2 is:

[0113]

[0114] Comparative Example 3

[0115] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0116] S1. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C. After vaporization, the mixture enters the reactor for reaction at 205°C and 0.3 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The fraction at 60-100°C is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0117] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:3.5:0.7;

[0118] The preparation of the solid acid catalyst comprises the following steps:

[0119] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.25 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 9% of the total volume of the mixed solution. Ammonia water was then added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate. After aging for 6.5 h, the precipitate was filtered, washed with deionized water three times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite support.

[0120] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soy lecithin, and the balance is deionized water;

[0121] (2) The Ce(OH)4-Al(OH)3 composite support was subjected to ultrasonic-magnetic field coupling treatment, with the ultrasonic power controlled at 100W, the ultrasonic frequency at 20kHz, and the DC magnetic field power at 1200W. After treatment for 2.5 minutes, the support was immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio controlled at 1:12. After immersion for 40 minutes, the support was filtered and placed in a vacuum drying oven at 15Pa and 30°C for low-temperature vacuum drying. The support was then calcined at 550°C to obtain a solid acid catalyst.

[0122] The reaction process of step S1 is:

[0123]

[0124] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 95° C., add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.45, heat it to 160° C., maintain for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0125] The reaction process of step S2 is:

[0126]

[0127] Comparative Example 4

[0128] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0129] S1. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C. After vaporization, the mixture enters the reactor for reaction at 205°C and 0.3 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The fraction at 60-100°C is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0130] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:3.5:0.7;

[0131] The solid acid catalyst is a catalyst described in the literature (Lin Furong. Synthesis of 2-methyl-5-ethyl-pyridine by gas phase method [J]. Modern Chemical Industry, 2008 (11): 38-40. DOI: 10.3321 / j.issn: 0253-4320.2008.11.008.);

[0132] The reaction process of step S1 is:

[0133]

[0134] S2. Add 5-ethyl-2-pyridineethanol intermediate I into a high-pressure reactor, heat it to 95° C., add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.45, heat it to 160° C., maintain for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0135] The reaction process of step S2 is:

[0136]

[0137] Comparative Example 5

[0138] A method for synthesizing 5-ethyl-2-pyridineethanol comprises the following steps:

[0139] S1. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, and the reactor and vaporizer are heated to a specified temperature. Then, paraldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C. After vaporization, the mixture enters the reactor for reaction at 205°C and 0.3 MPa. After the reaction is completed, the reaction solution is collected, allowed to stand and decompose, and the organic phase is collected. The aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is distilled under reduced pressure. The fraction at 60-100°C is collected, and the fraction is further distilled to obtain 5-ethyl-2-pyridineethanol intermediate I;

[0140] The mass ratio of the paraldehyde, ammonia water and solid catalyst is 1:3.5:0.7;

[0141] The preparation of the solid acid catalyst comprises the following steps:

[0142] (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.25 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then an auxiliary agent was added at a total volume of 9% of the total volume of the mixed solution. Ammonia water was then added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate. After aging for 6.5 h, the precipitate was filtered, washed with deionized water three times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite support.

[0143] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soy lecithin, and the balance is deionized water;

[0144] (2) The Ce(OH)4-Al(OH)3 composite carrier was subjected to ultrasonic-magnetic field coupling treatment, with the ultrasonic power controlled at 100W, the ultrasonic frequency at 20kHz, and the DC magnetic field power at 1200W. After treatment for 2.5 minutes, it was immersed in a 5% sulfuric acid solution with a solid-liquid mass ratio controlled at 1:12. After immersion for 40 minutes, it was filtered and placed in a vacuum drying oven at 15Pa and 30℃ for low-temperature vacuum drying, and then calcined at 550℃ to obtain SO4 2- / (CeO2-Al2O3);

[0145] (3) Ultrasonic dispersion of nano-silica into a 50% ethanol solution, with a mass volume ratio of nano-silica to 50% ethanol of 1 g:110 mL, followed by addition of 6% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 35°C and 250 rpm for 14 h, centrifuging at 9000 rpm for 12 min, washing the precipitate four times with deionized water, and drying at 55°C to constant weight to obtain pre-modified nano-silica, which was added to a reactor, and a 350-fold toluene solution of the pre-modified nano-silica was added for ultrasonic dispersion, then heated to 75°C, and 0.8 times the mass of the precipitate of thionyl chloride was added, stirring at 350 rpm and 85°C for 45 min, then filtered, washed four times with deionized water, and dried at 45°C under vacuum for 11 h to obtain modified nano-silica;

[0146] (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica were added into a bead mill at a mass ratio of 25:1 and ground at 700 rpm for 25 min to obtain a solid acid catalyst;

[0147] The reaction process of step S1 is:

[0148]

[0149] S2. Add 5-ethyl-2-pyridineethanol intermediate I to a high-pressure reactor, add 37% formaldehyde solution, the mass ratio of 5-ethyl-2-pyridineethanol intermediate I to 37% formaldehyde solution is 1:0.45, heat to 160°C, maintain for 3 hours to complete the reaction, cool to room temperature, pour out the reaction solution, and directly distill it. First, use a water pump to reduce pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain a fraction, and finally distill out the product 5-ethyl-2-pyridineethanol.

[0150] The reaction process of step S2 is:

[0151]

[0152] Test Example 1:

[0153] The yield of 2-methyl-5-ethylpyridine in each example and comparative example was measured, and the results are shown in Table 1 below.

[0154] Table 1 Yield of 2-methyl-5-ethylpyridine in each embodiment and comparative example

[0155] Yield (%) Example 1 82.3 Example 2 86.5 Example 3 85.1 Comparative Example 1 79.8 Comparative Example 2 75.5 Comparative Example 3 73.4 Comparative Example 4 71.3

[0156] As can be seen from Table 1 above, the yields of 2-methyl-5-ethylpyridine in Examples 1 to 3 are significantly better than those in the comparative example, indicating that the solid acid catalyst of the present invention has good selectivity, can significantly improve the reaction activity, and the reaction conditions are suitable, which helps to promote the conversion of the raw materials and increase the yield of the product.

[0157] Test Example 2:

[0158] The effect of the amount of catalyst on the yield of 2-methyl-5-ethylpyridine was determined. The results are shown in Table 2 below.

[0159] Table 2 Effect of catalyst dosage on the yield of 2-methyl-5-ethylpyridine

[0160]

[0161]

[0162] As shown in Table 2 above, as the amount of the solid acid catalyst of the present invention increases, the yield of 2-methyl-5-ethylpyridine shows a trend of first increasing and then decreasing, and after the ratio is 1:0.8, the yield will not have an increasing trend, indicating that the solid acid catalyst of the present invention has a certain dosage effect, and when the addition amount is only 1:0.2, it has very high catalytic activity.

[0163] Test Example 3:

[0164] The yield of 5-ethyl-2-pyridineethanol was determined in each example and comparative example, and the test results are shown in Table 3 below. The single-pass yield in the table is calculated based on the 2-methyl-5-ethylpyridine fed into the reaction, and the total yield is calculated based on the consumed 2-methyl-5-ethylpyridine after deducting the recovered 2-methyl-5-ethylpyridine.

[0165] Table 3 Yield of 5-ethyl-2-pyridineethanol in each embodiment and comparative example

[0166] One-way yield (%) Total yield (%) Example 1 25.6 80.6 Example 2 26.1 81.2 Example 3 25.3 80.3 Comparative Example 5 19.8 70.8

[0167] As can be seen from Table 3 above, the single-pass yield and total yield of the reactions of Examples 1 to 3 are as high as 26.1 and 79.2, and are significantly better than those of Comparative Example 5, indicating that the improvement of the heating process in the present application can improve the utilization rate of the raw materials and thus increase the yield of the product.

[0168] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing 5-ethyl-2-pyridineethanol, characterized in that: The steps include: S1. A solid acid catalyst is loaded into a reactor continuously purged with nitrogen, the reactor and vaporizer are heated to a specified temperature, and then paraldehyde and ammonia are added together into the vaporizer for vaporization. After vaporization, the mixture enters the reactor for reaction. After completion of the reaction, the reaction solution is collected, allowed to stand and decompose, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, and the crude product is subjected to reduced pressure distillation. A fraction at 60-100° C. is collected, and the fraction is further rectified to obtain Intermediate I for preparing 5-ethyl-2-pyridineethanol; The reaction process of step S1 is: ； The preparation of the solid acid catalyst comprises the following steps: (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O were dissolved in deionized water to prepare a 0.2~0.3 mol / L mixed solution of aluminum nitrate and cerium nitrate, and then 7~11% of the total volume of the mixed solution was added as an additive. Ammonia water was then added dropwise while stirring until the pH of the system was 9~10 to obtain Ce(OH)4-Al(OH)3 precipitate. After aging for 6~7 h, the precipitate was filtered, washed with deionized water 2~4 times, and dried at 70~80°C to obtain a Ce(OH)4-Al(OH)3 composite support. The ingredients and corresponding weight percentages in the auxiliary agent are: 2-3% hydroxypropyl methylcellulose, 2-3% polyvinyl alcohol, 5-9% soy lecithin, and the balance is deionized water; (2) The Ce(OH)4-Al(OH)3 composite carrier was treated with ultrasonic-magnetic field coupling. After completion, it was immersed in 5% sulfuric acid solution with a solid-liquid mass ratio of 1:8~16. After immersion for 30~50 minutes, it was filtered and placed in a vacuum drying oven for low-temperature vacuum drying. Then, it was calcined to obtain SO4 2- / (CeO2-Al2O3); (3) Ultrasonic dispersion of nano-silica in 50% ethanol solution, then adding dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 30-40°C and 200-300 rpm for 12-16 hours, centrifuging at 8000-10000 rpm for 10-15 minutes, washing the precipitate with deionized water 3-5 times, and drying at 50-60°C to constant weight to obtain pre-modified nano-silica, adding it to a reactor, adding toluene solution for ultrasonic dispersion, heating to 70-80°C, adding 0.7-1 times the mass of the precipitate with thionyl chloride, stirring at 300-400 rpm and 80-90°C for 40-50 minutes, filtering, washing with deionized water 3-5 times, and drying at 40-50°C under vacuum conditions for 10-12 hours to obtain modified nano-silica; (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica were added into a bead mill at a mass ratio of 20-30:1 and ground at 500-1000 rpm for 20-30 min to obtain a solid acid catalyst; S2. The intermediate I for preparing 5-ethyl-2-pyridineethanol is added to a high-pressure reactor, the temperature is raised to 90-100° C., 37% formaldehyde solution is added, the temperature is raised to 160° C., and the reaction is maintained for 3 hours to complete the reaction. The reaction mixture is cooled to room temperature, the reaction solution is poured out, and distilled directly. Unreacted formaldehyde and water therein are first evaporated under reduced pressure using a water pump, and then the unreacted intermediate I for preparing 5-ethyl-2-pyridineethanol is collected to obtain a fraction, and finally the product 5-ethyl-2-pyridineethanol is distilled off.

2. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, characterized in that: The mass ratio of paraldehyde, aqueous ammonia and solid catalyst in step S1 is 1:3-4:0.2-1.

2.

3. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, characterized in that: The temperature of the vaporizer in step S1 is 160-180°C; The temperature of the reactor is 175-235°C; The reaction pressure is controlled at 0.2-0.4 MPa.

4. The method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, wherein The ultrasonic power in step (2) is 50-150 W, the ultrasonic frequency is 20 kHz, the DC magnetic field power is 1000-1500 W, and the treatment time is 2-3 min; During the low-temperature vacuum drying process, the vacuum degree is controlled to be 10-20 Pa and the temperature is 20-40° C. The calcination temperature is 500-600°C.

5. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, characterized in that: The mass volume ratio of the nano-silica and 50% ethanol described in step (3) is 1g:90~140mL; The amount of dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride added is 4-8% of the total volume of 50% ethanol; The mass ratio of the pre-modified nano-silica to toluene is 1:300-400.

6. The method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, wherein: The mass ratio of the intermediate I for preparing 5-ethyl-2-pyridineethanol described in step S2 to the 37% formaldehyde solution is 1:0.3~0.

6.

7. The method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, wherein: The reaction process of step S2 is: .

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