Synthesis method of 5-ethyl-2-pyridylethanol

Abstract

The invention discloses a synthesis method of 5-ethyl-2-pyridylethanol, and belongs to the technical field of organic synthesis. The invention provides a synthesis method of 5-ethyl-2-pyridylethanol, which takes a special solid acid catalyst as a catalyst, takes paraldehyde and ammonia gas as raw materials, and adjusts the dosage, vaporization temperature, reaction temperature and reaction pressure of the raw materials and the catalyst, so that the final yield of 2-methyl-5-ethylpyridine reaches up to 86.5%. By adjusting reaction conditions, the obtained 2-methyl-5-ethylpyridine reacts with a 37% methanol aqueous solution, and the total yield of the final product 5-ethyl-2-pyridineethanol is up to 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, which has a good therapeutic effect on the treatment of non-insulin-dependent diabetes mellitus. 5-ethyl-2-pyridineethanol is an important intermediate for the synthesis of this drug, and the study of its synthesis process is of great significance.

[0003] 5-Ethyl-2-pyridineethanol is synthesized in two steps. First, acetaldehyde or triacetaldehyde reacts with ammonia to synthesize the intermediate 2-methyl-5-ethylpyridine, and then 2-methyl-5-ethylpyridine reacts with formaldehyde aqueous solution to produce the target product. The synthesis process of both substances has a great influence on 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 this type of product in my country is relatively weak at present, and the relevant research is not in-depth enough, and the technology cannot reach the international level, and large-scale production has not been formed. As the research and development efforts of my country's fine chemical products are strengthened, the consumption of these two pyridine derivatives is constantly increasing, but the main source is still import, and the domestic production scale is small. Strengthening the research and development of this product and building a large-scale production device will effectively reduce the dependence of my country's pyridine series products on imports and promote the research and development of downstream products. Therefore, the research on the synthesis process of 5-ethyl-2-pyridineethanol and its intermediates has important economic and social benefits.

[0005] However, most of the current synthesis processes use liquid phase synthesis, which generally has the problems of 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 the cost. However, the gas phase method is not 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 prior art. Summary of the invention

[0007] The purpose of the invention is to provide a method for synthesizing 5-ethyl-2-pyridineethanol in view of 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. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization, and the vaporized product enters the reactor for reaction. After the reaction is completed, the reaction liquid is collected, allowed to stand for stratification, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and a fraction of 60 to 100° C. is collected, and the fraction is rectified again 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the fraction, and finally evaporate 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 are dissolved in deionized water to prepare a 0.2-0.3 mol / L aluminum nitrate and cerium nitrate mixed solution, and then 7-11% of the total volume of the mixed solution is added with an auxiliary agent, and then ammonia water is added dropwise while stirring until the pH of the system is 9-10 to obtain Ce(OH)4-Al(OH)3 precipitation, and the mixture is aged for 6-7 hours and then filtered, washed with deionized water for 2-4 times, and dried at 70-80°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

[0018] (2) The Ce(OH)4-Al(OH)3 composite carrier is subjected to ultrasonic-magnetic field coupling treatment, and then immersed in a 5% sulfuric acid solution, with the solid-liquid mass ratio controlled at 1:8-16. After immersion for 30-50 minutes, the composite carrier is 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, 200-300rpm for 12-16h, centrifuging at 8000-10000rpm for 10-15min, washing the precipitate with deionized water for 3-5 times, and drying at 50-60°C to constant weight to obtain pre-modified nano-silica, adding it to a reaction kettle, adding toluene solution for ultrasonic dispersion, heating to 70-80°C, adding 0.7-1 times the mass of thionyl chloride, stirring at 300-400rpm, 80-90°C for 40-50min, filtering, washing with deionized water for 3-5 times, and drying at 40-50°C under vacuum for 10-12h 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 to 30:1, and ground at 500 to 1000 rpm for 20 to 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 to 150 W, the ultrasonic frequency is 20 kHz, the DC magnetic field power is 1000 to 1500 W, and the treatment time is 2 to 3 min;

[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-silicon dioxide 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 silicon dioxide 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 dosage 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%. Then, by adjusting the reaction conditions, the obtained 2-methyl-5-ethylpyridine is reacted with a 37% methanol aqueous solution, and finally achieving a total yield of 5-ethyl-2-pyridineethanol as high as 81.2%.

[0035] First, under the action of the auxiliary agent and the precipitant, a 5-ethyl-2-pyridineethanol composite carrier is formed by coprecipitation, wherein the presence of the auxiliary agent can form a steric hindrance effect, prevent precipitation agglomeration, change the stacking properties of the particles, increase the pore volume after subsequent calcination, and thus increase the specific surface area of ​​the carrier. The ultrasonic-DC magnetic field coupling treatment and the low-temperature vacuum drying treatment cooperate with each other to change the microporous structure of the carrier, increase the porosity, and improve the selectivity of the solid acid catalyst and the conversion rate of the product. After the nano-silica is modified by dimethyloctadecyl [3-(trimethoxysilyl)propyl] ammonium chloride and thionyl chloride, it has very high surface properties, stability and dispersibility, and the modified nano-silica is then mixed with to further improve the catalytic activity and stability of the catalyst.

[0036] The solid acid catalyst is used for 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 the production cost.

[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 described embodiments 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 work 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 supplied with nitrogen, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 160°C, and the mixture is allowed to enter the reactor for reaction at 175°C and 0.2MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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 aluminum nitrate and cerium nitrate mixed solution, and then an auxiliary agent was added to the total volume of the mixed solution at 7%, and then ammonia water was added dropwise while stirring until the pH of the system was 9 to obtain Ce(OH)4-Al(OH)3 precipitate, which was aged for 6 hours and then filtered, washed twice with deionized water, and dried at 70-80°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

[0046] The ingredients and corresponding weight percentages in the auxiliary agent are: 2% hydroxypropyl methylcellulose, 2% polyvinyl alcohol, 5% soybean 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 the 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°C for low-temperature vacuum drying, and then calcined at 500°C to obtain SO4 2- / (CeO2-Al2O3);

[0048] (3) Ultrasonic dispersion of nano-silica in a 50% ethanol solution, the mass volume ratio of nano-silica to 50% ethanol being 1 g:90 mL, then adding 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 3 times with deionized water, and drying at 50°C to constant weight to obtain pre-modified nano-silica, adding the solution to a reaction kettle, adding 300 times of toluene solution of the pre-modified nano-silica to ultrasonically disperse the solution, heating the solution to 70°C, adding 0.7 times of thionyl chloride mass of the precipitate, stirring at 300 rpm and 80°C for 40 min, filtering the solution, washing the solution 3 times with deionized water, and drying the solution 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, keep 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the 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, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C, and the mixture is allowed to enter the reactor for reaction at 205°C and 0.3MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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 mixed solution, and then ammonia water was added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate, which was aged for 6.5 h and then filtered, washed with deionized water 3 times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

[0061] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soybean 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 2.5min, it was immersed in a 5% sulfuric acid solution, with the solid-liquid mass ratio controlled at 1:12. After immersion for 40min, it was filtered and placed in a vacuum drying oven at 15Pa and 30°C for low-temperature vacuum drying, and then calcined at 550°C to obtain SO4 2- / (CeO2-Al2O3);

[0063] (3) Ultrasonic dispersion of nano-silica in a 50% ethanol solution, the mass volume ratio of nano-silica to 50% ethanol being 1 g:110 mL, and then adding 6% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 35°C, 250 rpm for 14 h, centrifuging at 9000 rpm for 12 min, washing the precipitate with deionized water 4 times, and drying at 55°C to constant weight to obtain pre-modified nano-silica, adding the solution to a reaction kettle, adding 350 times the toluene solution of the pre-modified nano-silica to ultrasonically disperse the solution, heating the solution to 75°C, adding 0.8 times the mass of the precipitate with thionyl chloride, stirring the solution at 350 rpm, 85°C for 45 min, filtering the solution, washing the solution with deionized water 4 times, and drying the solution 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, keep 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the fraction, and finally evaporate 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 supplied with nitrogen, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 180°C, and the mixture is allowed to enter the reactor for reaction at 235°C and 0.4MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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 of 11% of the total volume of the mixed solution was added, and then ammonia water was added dropwise while stirring until the pH of the system was 10 to obtain Ce(OH)4-Al(OH)3 precipitate, and the mixture was aged for 7 hours and filtered, washed with deionized water 4 times, and dried at 80°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

[0076] The ingredients and corresponding weight percentages in the auxiliary agent are: 3% hydroxypropyl methylcellulose, 3% polyvinyl alcohol, 9% soybean 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 the 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°C for low-temperature vacuum drying, and then calcined at 600°C to obtain SO4 2- / (CeO2-Al2O3);

[0078] (3) Ultrasonic dispersion of nano-silica in a 50% ethanol solution, the mass volume ratio of nano-silica to 50% ethanol being 1 g:140 mL, then adding 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 with deionized water for 5 times, and drying at 60°C to constant weight to obtain pre-modified nano-silica, adding the solution to a reaction kettle, adding 400 times of toluene solution of the pre-modified nano-silica to ultrasonically disperse the solution, heating the solution to 80°C, adding 1 times of thionyl chloride in weight of the precipitate, stirring at 400 rpm and 90°C for 50 min, filtering the solution, washing the solution with deionized water for 5 times, 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, keep it for 3 hours to complete the reaction, cool it down to room temperature, pour out the reaction solution, and distill it directly. First, use a water pump to reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the 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, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C, and the mixture is allowed to enter the reactor for reaction at 205°C and 0.3MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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 mixed solution, and then ammonia water was added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate, which was aged for 6.5 h and then filtered, washed with deionized water 3 times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

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

[0092] (2) The Ce(OH)4-Al(OH)3 composite carrier was immersed in a 5% sulfuric acid solution, with the 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°C for low-temperature vacuum drying. Then, it was calcined at 550°C to obtain SO4 2- / (CeO2-Al2O3);

[0093] (3) Ultrasonic dispersion of nano-silica in a 50% ethanol solution, the mass volume ratio of nano-silica to 50% ethanol being 1 g:110 mL, and then adding 6% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 35°C, 250 rpm for 14 h, centrifuging at 9000 rpm for 12 min, washing the precipitate with deionized water 4 times, and drying at 55°C to constant weight to obtain pre-modified nano-silica, adding the solution to a reaction kettle, adding 350 times the toluene solution of the pre-modified nano-silica to ultrasonically disperse the solution, heating the solution to 75°C, adding 0.8 times the mass of the precipitate with thionyl chloride, stirring the solution at 350 rpm, 85°C for 45 min, filtering the solution, washing the solution with deionized water 4 times, and drying the solution 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, keep 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the fraction, and finally evaporate 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, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C, and the mixture is allowed to enter the reactor for reaction at 205°C and 0.3MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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 mixed solution, and then ammonia water was added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate, which was aged for 6.5 h and then filtered, washed with deionized water 3 times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

[0106] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soybean 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 2.5min, it was immersed in a 5% sulfuric acid solution, with the solid-liquid mass ratio controlled at 1:12. After immersion for 40min, it was filtered and placed in a vacuum drying oven at 15Pa and 30°C for low-temperature vacuum drying, and then calcined at 550°C to obtain SO4 2- / (CeO2-Al2O3);

[0108] (3) SO4 2- / (CeO2-Al2O3) and nano-silicon dioxide 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, keep 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the fraction, and finally evaporate 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, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C, and the mixture is allowed to enter the reactor for reaction at 205°C and 0.3MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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 mixed solution, and then ammonia water was added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate, which was aged for 6.5 h and then filtered, washed with deionized water 3 times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

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

[0121] (2) The Ce(OH)4-Al(OH)3 composite carrier was subjected to ultrasonic-magnetic field coupling treatment, with the ultrasonic power controlled at 100 W, the ultrasonic frequency at 20 kHz, and the DC magnetic field power at 1200 W. After treatment for 2.5 min, the carrier was immersed in a 5% sulfuric acid solution, with the solid-liquid mass ratio controlled at 1:12. After immersion for 40 min, the carrier was filtered and placed in a vacuum drying oven at 15 Pa and 30 ° C for low-temperature vacuum drying. The carrier 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, keep 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the fraction, and finally evaporate 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, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C, and the mixture is allowed to enter the reactor for reaction at 205°C and 0.3MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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, keep 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the fraction, and finally evaporate 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, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization. The temperature of the vaporizer is 170°C, and the mixture is allowed to enter the reactor for reaction at 205°C and 0.3MPa. After the reaction is completed, the reaction liquid is collected, allowed to stand and stratified, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and the 60-100°C fraction is collected. The fraction is distilled again 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 mixed solution, and then ammonia water was added dropwise while stirring until the pH of the system was 9.5 to obtain a Ce(OH)4-Al(OH)3 precipitate, which was aged for 6.5 h and then filtered, washed with deionized water 3 times, and dried at 75°C to obtain a Ce(OH)4-Al(OH)3 composite carrier;

[0143] The ingredients and corresponding weight percentages in the auxiliary agent are: 2.5% hydroxypropyl methylcellulose, 2.5% polyvinyl alcohol, 7% soybean 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 2.5min, it was immersed in a 5% sulfuric acid solution, with the solid-liquid mass ratio controlled at 1:12. After immersion for 40min, it was filtered and placed in a vacuum drying oven at 15Pa and 30°C for low-temperature vacuum drying, and then calcined at 550°C to obtain SO4 2- / (CeO2-Al2O3);

[0145] (3) Ultrasonic dispersion of nano-silica in a 50% ethanol solution, the mass volume ratio of nano-silica to 50% ethanol being 1 g:110 mL, and then adding 6% dimethyloctadecyl[3-(trimethoxysilyl)propyl]ammonium chloride, stirring at 35°C, 250 rpm for 14 h, centrifuging at 9000 rpm for 12 min, washing the precipitate with deionized water 4 times, and drying at 55°C to constant weight to obtain pre-modified nano-silica, adding the solution to a reaction kettle, adding 350 times the toluene solution of the pre-modified nano-silica to ultrasonically disperse the solution, heating the solution to 75°C, adding 0.8 times the mass of the precipitate with thionyl chloride, stirring the solution at 350 rpm, 85°C for 45 min, filtering the solution, washing the solution with deionized water 4 times, and drying the solution 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 into 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 the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the 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 embodiment 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 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] It can be concluded from Table 2 that with the increase in the amount of the solid acid catalyst of the present invention, the yield of 2-methyl-5-ethylpyridine shows a trend of first increasing and then decreasing, and the yield will not have an increasing trend after the ratio is 1:0.8, 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 a very high catalytic activity.

[0163] Test Example 3:

[0164] The yield of 5-ethyl-2-pyridineethanol in each embodiment and comparative example was measured, and the test results are shown in Table 3. The single-pass yield in the table is calculated based on the 2-methyl-5-ethylpyridine put 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] It can be seen from Table 3 above that 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, thereby increasing 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. The solid acid catalyst is loaded into a reactor continuously supplied with nitrogen, the reactor and the vaporizer are heated to a specified temperature, and then triacetaldehyde and ammonia are added together into the vaporizer for vaporization, and the vaporized product enters the reactor for reaction. After the reaction is completed, the reaction liquid is collected, allowed to stand for stratification, the organic phase is collected, the aqueous phase is extracted twice with dichloromethane, the organic phases are combined, the dichloromethane is evaporated, the crude product is distilled under reduced pressure, and a fraction of 60 to 100° C. is collected, and the fraction is rectified again to obtain 5-ethyl-2-pyridineethanol intermediate I; 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 reduce the pressure to evaporate the unreacted formaldehyde and the water therein, then collect the unreacted 5-ethyl-2-pyridineethanol intermediate I to obtain the fraction, and finally evaporate the product 5-ethyl-2-pyridineethanol.

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. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, characterized in that: The preparation of the solid acid catalyst in step S1 comprises the following steps: (1) Al(NO3)3·9H2O and Ce(NO3)3·6H2O are dissolved in deionized water to prepare a 0.2-0.3 mol / L aluminum nitrate and cerium nitrate mixed solution, and then 7-11% of the total volume of the mixed solution is added with an auxiliary agent, and then ammonia water is added dropwise while stirring until the pH of the system is 9-10 to obtain Ce(OH)4-Al(OH)3 precipitate, and the precipitate is filtered after aging for 6-7 hours, washed with deionized water for 2-4 times, and dried at 70-80°C to obtain a Ce(OH)4-Al(OH)3 composite carrier; (2) The Ce(OH)4-Al(OH)3 composite carrier is subjected to ultrasonic-magnetic field coupling treatment, and then immersed in a 5% sulfuric acid solution, with the solid-liquid mass ratio controlled at 1:8-16. After immersion for 30-50 minutes, the composite carrier is filtered and placed in a vacuum drying oven for low-temperature vacuum drying, and then 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, 200-300rpm for 12-16h, centrifuging at 8000-10000rpm for 10-15min, washing the precipitate with deionized water for 3-5 times, and drying at 50-60°C to constant weight to obtain pre-modified nano-silica, adding it to a reaction kettle, adding toluene solution for ultrasonic dispersion, heating to 70-80°C, adding 0.7-1 times the mass of thionyl chloride, stirring at 300-400rpm, 80-90°C for 40-50min, filtering, washing with deionized water for 3-5 times, and drying at 40-50°C under vacuum for 10-12h to obtain modified nano-silica; (4) SO4 2- / (CeO2-Al2O3) and modified nano-silica are added into a bead mill in a mass ratio of 20 to 30:1, and ground at 500 to 1000 rpm for 20 to 30 minutes to obtain a solid acid catalyst.

5. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 4, characterized in that: The components and corresponding weight percentages of the auxiliary agent in step (1) are: 2-3% hydroxypropyl methylcellulose, 2-3% polyvinyl alcohol, 5-9% soybean lecithin, and the balance is deionized water.

6. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 4, characterized in that: 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; 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.

7. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 4, characterized in that: The mass volume ratio of the nano-silicon dioxide to 50% ethanol in step (3) is 1 g: 90-140 mL; 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 silicon dioxide to toluene is 1:300-400.

8. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, characterized in that: The reaction process of step S1 is:

9. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, characterized in that: 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.

10. A method for synthesizing 5-ethyl-2-pyridineethanol according to claim 1, characterized in that: The reaction process of step S2 is:

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