Preparation method of etocrilene

Abstract

The invention relates to the technical field of preparation of etocrilene, and discloses a preparation method of etocrilene, which sequentially comprises the steps of condensation reaction, rough preparation, refining, drying and packaging. According to the preparation method of the etocrilene provided by the invention, the vacuum degree and the temperature are synergistically optimized, and the reaction time is shortened and the generation of by-products is inhibited mainly by applying the vacuum degree of-0.088 MPa, controlling the temperature in stages, reducing the reaction activation energy and promoting the full contact of ethyl cyanoacetate and benzophenone. The vacuum environment can timely remove moisture generated by the reaction and push the balance to move towards the positive reaction direction, so that the yield is obviously improved. By optimizing the raw material ratio, the nucleophilic activity of benzophenone can be enhanced by a composite catalytic system of acetic acid and ammonium acetate, so that the raw material conversion rate is greatly improved compared with that of a traditional process. Through the synergistic effect of the processes of all the steps, the problems of low purity and insufficient yield in the prior art are systematically solved.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of etocrylene, in particular to a method for preparing etocrylene. Background Art

[0002] Etocrylene (ETO, ethyl 2-cyano-3,3-diphenylacrylate) is an important cosmetic ingredient widely used in sunscreens, UV absorbers, and other fields. The conjugated system in its molecular structure enables it to effectively absorb UVB rays, making it a core ingredient in the production of highly effective sunscreen products. As consumers demand greater safety and efficacy in cosmetics, higher demands are being placed on the purity and yield of Etocrylene. Existing Etocrylene preparation processes have the following drawbacks:

[0003] Insufficient condensation reaction efficiency: In the traditional process, the condensation reaction of ethyl cyanoacetate and benzophenone is carried out under normal pressure, with a long reaction time (the total reaction time often exceeds 20 hours), and a high proportion of by-products (such as benzophenone self-polymerization products), resulting in low raw material utilization and a yield generally lower than 80%.

[0004] Incomplete impurity removal during the refining process: Existing technologies use unmodified activated carbon or a single solvent for refining, which has limited adsorption capacity for reaction byproducts (such as ammonium acetate and unreacted benzophenone). For example, unmodified activated carbon has a low adsorption value for methylene blue, making it difficult to effectively remove color and turbidity impurities. This results in a low purity finished product that cannot meet the requirements of high-end cosmetic raw materials.

[0005] Based on this, the present invention further improves the existing technology to increase the purity and yield of etoclopramide products. Summary of the Invention

[0006] In view of the problems in the prior art, the present invention provides a method for preparing etoclopramide.

[0007] The technical solution adopted by the present invention to solve the technical problem is: a preparation method of etoclopramide, which comprises the steps of condensation reaction, crude preparation, refining, drying and packaging.

[0008] Condensation reaction: Add acetic acid, ethyl cyanoacetate, benzophenone and ammonium acetate to an enameled reactor, first heat up for pre-reaction, then heat up and apply vacuum until distillation appears on the condenser, then start counting. When no distillation appears, continue heating and keep warm for reaction. The total reaction time is 15-18 hours. After the reaction is completed, cool down under vacuum, add water, stir and separate the layers, and transfer the oil layer to a crude reactor.

[0009] Crude preparation: Distill under vacuum until there is no fraction, replace with nitrogen, add industrial-grade ethanol, reflux to dissolve, cool in sections, and centrifuge to obtain the crude product;

[0010] Refining: Pump ethanol into the refining kettle, add the crude product, heat and reflux to dissolve, add pharmaceutical grade activated carbon for adsorption, introduce nitrogen for bubbling and stirring, filter hot and reflux to dissolve, cool in stages, and centrifuge to obtain the refined product;

[0011] Drying and packaging: Drying is carried out in a double-cone dryer with hot water circulation, and the internal pressure of the dryer is controlled. The finished product is packaged after passing the inspection.

[0012] As a further technical solution, the amount of each raw material added in the condensation reaction is: 150 kg acetic acid, 360 kg ethyl cyanoacetate, 550 kg benzophenone and 50 kg ammonium acetate;

[0013] The temperature of the pre-reaction stage of the condensation reaction is 60-70°C and maintained for 1 hour;

[0014] The main reaction stage of the condensation reaction is first heated to 80-84°C, and a vacuum of -0.088 MPa is applied. After there is no fraction, the temperature is raised to 88-92°C and kept for reaction for 4 hours;

[0015] After the condensation reaction is completed, the temperature is lowered to below 80° C. in vacuum, and 400 kg of water is added, stirred, and separated into layers.

[0016] As a further technical solution, the crude step is distilled at a vacuum of -0.09 MPa to 78-80°C without distillate, and after nitrogen replacement, 900±50 kg of industrial grade ethanol is added;

[0017] The stepwise cooling process of the roughing step is: firstly cooling to 40-45°C, keeping warm for 3-4 minutes, and then cooling to 10-15°C.

[0018] As a further technical solution, in the refining step, 900±50 kg of ethanol is pumped into the refining kettle, and the temperature is raised to 75-78° C. to reflux and dissolve the clear solution;

[0019] In the refining step, 3-5 kg ​​of pharmaceutical grade activated carbon is added for adsorption for 30-40 minutes, and nitrogen gas with a flow rate of 0.6-1.0 m³ / h is simultaneously introduced for bubbling and stirring;

[0020] The hot filtration accuracy of the refining step is 6-10 μm, and the filtration pressure is maintained at 0.1-0.2 MPa;

[0021] The stepwise cooling process of the refining step is: firstly cooling to 40-45°C, keeping warm for 3-4 minutes, and then cooling to 15-20°C.

[0022] As a further technical solution, the preparation method of the pharmaceutical grade activated carbon comprises the following steps:

[0023] Raw material pretreatment: crush coconut shells to a particle size of 2-5 mm, wash with deionized water three times to remove impurities, and dry at 120°C until the moisture content is less than 5%;

[0024] High-temperature activation: The pretreated coconut shells are fed into a rotary kiln and heated at 10°C / min to 850-870°C in a nitrogen atmosphere. Steam is introduced for activation for 2.5-3 hours, during which the pressure in the kiln is maintained at -0.01 MPa to obtain the activated product.

[0025] Acid washing and purification: After cooling the activated product, soak it in 10-12% hydrochloric acid solution for 2 hours, filter it, wash it with deionized water until it is neutral, and dry it at 150°C for 6 hours;

[0026] Crushing and screening: After drying, the material is crushed to 80-120 mesh, magnetic separation is used to remove ferromagnetic impurities, and sealed and packaged for later use.

[0027] As a further technical solution, the water vapor flow rate is 5-8 kg / h.

[0028] As a further technical solution, the pharmaceutical grade activated carbon is modified as follows:

[0029] Silver nitrate loading modification: Pharmaceutical grade activated carbon was immersed in a 5-6% silver nitrate ethanol solution, ultrasonically dispersed for 30 minutes, and then allowed to stand for 2 hours. After filtration, it was vacuum-dried at 120°C for 3 hours to obtain a preliminary modified activated carbon with a silver loading of 0.5-1.0%.

[0030] Ozone oxidation modification: Place the preliminarily modified activated carbon in a reactor, introduce ozone gas with an ozone concentration of 80-100 mg / L, treat at room temperature for 1.5-2 hours, maintain a gas flow rate of 200-300 mL / min, then discharge the material and let it stand for 4-5 hours to obtain.

[0031] As a further technical solution, the solid-to-liquid ratio of the pharmaceutical-grade activated carbon and the silver nitrate ethanol solution is 1:5-6.

[0032] As a further technical solution, the frequency of the ultrasonic dispersion is 40kHz and the power is 600W;

[0033] The vacuum degree of the vacuum drying is 0.1 Pa.

[0034] As a further technical solution, the drying step is carried out in a 2000L double cone dryer, using 60-80°C hot water circulation drying for 4 hours, and controlling the internal pressure of the dryer to ≤-0.095MPa;

[0035] The finished product testing standard is loss on drying ≤ 0.5%.

[0036] Beneficial effects of the present invention:

[0037] In the preparation method of etocrylene provided herein, vacuum and temperature are synergistically optimized. By applying a vacuum of -0.088 MPa and controlling the temperature in stages, the activation energy of the reaction is reduced, promoting sufficient contact between ethyl cyanoacetate and benzophenone, shortening the reaction time, and suppressing the formation of byproducts. The vacuum environment promptly removes moisture generated by the reaction, shifting the equilibrium toward the forward reaction and significantly improving yield.

[0038] The present invention optimizes the raw material ratio: the composite catalytic system of acetic acid and ammonium acetate can enhance the nucleophilic activity of benzophenone, so that the raw material conversion rate is greatly improved compared with the traditional process.

[0039] The present invention can significantly improve the purity and yield of the product by coordinating the crude and refined stages. It mainly includes: staged cooling crystallization: through a staged cooling process of first cooling to 40-45°C for insulation and then cooling to 10-15°C, uniform crystal particles are formed, the mother liquor entrainment loss is reduced, and the crude product yield is increased by 5%-8%.

[0040] In addition, the present invention uses specially prepared modified activated carbon to further improve the purity and yield of the product; wherein, silver nitrate loading: through the silver nitrate ethanol solution impregnation, the activated carbon surface loaded with Ag + , forming active sites, adsorbing polar impurities (such as acetate ions) through ion exchange and complexation; Ozone oxidation: Ozone treatment generates a large number of hydroxyl and carboxyl functional groups on the surface of activated carbon, greatly increasing the specific surface area, and effectively removing color and turbidity through the synergistic effect of physical adsorption and chemical adsorption, and significantly improving the purity of the finished product.

[0041] The present invention systematically solves the problems of low purity and insufficient yield in the prior art through the synergistic effect of each step of the process, and has significant economic value and environmental benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 This is a process flow chart for the preparation of etoclopramide;

[0043] Figure 2 Diagram of the synthesis mechanism of Yililin. DETAILED DESCRIPTION

[0044] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0045] The present invention provides a method for preparing etocrylene, comprising the following steps:

[0046] a) Condensation reaction: 150 kg of acetic acid, 360 kg of ethyl cyanoacetate, 550 kg of benzophenone and 50 kg of ammonium acetate were added to an enameled reactor, the temperature was raised to 60-70°C and maintained for 1 hour for preliminary reaction, then the temperature was raised to 80-84°C and a vacuum of -0.088 MPa was applied until distillate appeared on the condenser and the time was counted. When no distillate appeared, the temperature was raised to 88-92°C and the temperature was kept for 4 hours, with a total reaction time of 15-18 hours. After the reaction was completed, the temperature was lowered to below 80°C in vacuum, 400 kg of water was added, stirred and separated, and the oil layer was transferred to a crude reactor.

[0047] b) Crude preparation: Distill under a vacuum of -0.09 MPa until no fraction is found at 78-80°C. After nitrogen displacement, add 900±50 kg of industrial-grade ethanol and reflux at 75-78°C to dissolve the clear solution. Cool the mixture in stages, first to 40-45°C, hold for 3-4 minutes, then to 10-15°C. Centrifuge to obtain the crude product.

[0048] c) Refining: Pump 900±50kg of ethanol into the refining kettle, add the crude product and heat it to 75-78℃ for reflux dissolution, add 3-5kg of pharmaceutical grade activated carbon for adsorption for 30-40 minutes, and simultaneously introduce the flow rate at 0.6-1.0m 3 / h nitrogen bubbling and stirring, hot filtration (filtration accuracy 6-10μm, pressure 0.1-0.2MPa) after reflux dissolution, stage by stage cooling, first to 40-45℃, keep warm for 3-4min, then to 15-20℃, centrifuge to obtain fine products; the pharmaceutical grade activated carbon is prepared by the following method:

[0049] c1) Raw material pretreatment: Coconut shells were crushed to a particle size of 2-5 mm, washed three times with deionized water to remove impurities, and dried at 120°C until the moisture content was less than 5%;

[0050] c2) High-temperature activation: The pretreated coconut shells were placed in a rotary kiln, heated at 10°C / min to 850-870°C in a nitrogen atmosphere, and activated by introducing 5-8 kg / h of steam for 2.5-3 hours while maintaining the pressure in the kiln at -0.01 MPa to obtain an activated product;

[0051] c3) Acid washing and purification: After cooling, the activated product was soaked in 10-12% hydrochloric acid solution for 2 hours, filtered, washed with deionized water until neutral, and dried at 150°C for 6 hours;

[0052] c4) Crushing and screening: After drying, the material is crushed to 80-120 mesh and magnetically separated to remove ferromagnetic impurities;

[0053] c5) Modification: The activated carbon was immersed in a 5-6% silver nitrate ethanol solution (solid-to-liquid ratio of 1:5-6), ultrasonically dispersed at 40 kHz and 600 W for 30 minutes, allowed to stand for 2 hours, filtered, and dried at 120°C and 0.1 Pa vacuum for 3 hours to obtain a preliminary modified activated carbon with a silver loading of 0.5-1.0%. 80-100 mg / L ozone gas (flow rate of 200-300 mL / min) was then introduced, treated at room temperature for 1.5-2 hours, and allowed to stand for 4-5 hours.

[0054] d) Drying and packaging: Dry in a 2000L double-cone dryer with 60-80℃ hot water for 4 hours. Control the internal pressure of the dryer to be ≤-0.095MPa. The finished product shall pass the inspection (purity ≥99.0%, loss on drying ≤0.5%) and then be packaged.

[0055] The following are specific embodiments:

[0056] Example 1

[0057] Specifically include:

[0058] (1) Condensation reaction: Heat to 65°C and maintain for 1 hour, then heat to 82°C, apply -0.088 MPa vacuum until distillate appears and start counting. When no distillate appears, heat to 90°C and keep warm for 4 hours, with a total reaction time of 16 hours. After the reaction is completed, cool to 75°C in vacuum, add 400 kg of water, stir and separate, and transfer the oil layer into a crude kettle.

[0059] (2) Crude preparation: Distill the mixture under a vacuum of -0.09 MPa to 79°C until no fraction is found. After nitrogen replacement, add 900 kg of industrial-grade ethanol and reflux at 76°C to dissolve the mixture. Then cool the mixture in stages to 42°C and keep the temperature for 3 minutes. Then cool the mixture to 12°C and centrifuge to obtain the crude product.

[0060] (3) Refining: Pump in 900 kg of ethanol, add the crude product and reflux at 76 ° C to dissolve it, add 4 kg of pharmaceutical grade activated carbon and adsorb it for 35 minutes, then pass 0.8 m 3 / h nitrogen bubbling and stirring, hot filtration (precision 8μm, pressure 0.15MPa) and then reflux to dissolve the clear solution, cooling in stages to 43℃ and keeping warm for 3min, then cooling to 18℃ and centrifuging to obtain the fine product.

[0061] (4) Preparation of activated carbon:

[0062] c1) Coconut shells were crushed to 3 mm, washed with deionized water three times, and dried at 120°C to a moisture content of 4%;

[0063] c2) heating to 860°C at 10°C / min, introducing 6kg / h of steam for activation for 2.8 hours, with the furnace pressure at -0.01MPa;

[0064] c3) After cooling, soak in 11% hydrochloric acid solution for 2 hours, wash until neutral, and dry at 150°C for 6 hours;

[0065] c4) crushing to 100 mesh and removing impurities by magnetic separation;

[0066] c5) The sample was immersed in 5.5% silver nitrate ethanol solution at a solid-to-liquid ratio of 1:5.5, and ultrasonically dispersed at 40 kHz and 600 W for 30 minutes. The sample was allowed to stand for 2 hours, filtered, and vacuum dried at 120°C and 0.1 Pa for 3 hours, resulting in a silver loading of 0.8%. The sample was then passed through 90 mg / L ozone gas (flow rate 250 mL / min) at room temperature for 1.8 hours, and allowed to stand for 4.5 hours.

[0067] (5) Drying and packaging: Dry in a double-cone dryer with hot water circulation at 65°C for 4 hours, with an internal pressure of -0.096MPa. Package after passing the test.

[0068] Example 2

[0069] Specifically include:

[0070] (1) Condensation reaction: Heat to 60°C and maintain for 1 hour, then heat to 80°C, apply vacuum until distillate appears and start counting. When no distillate appears, heat to 88°C and keep warm for 4 hours. The total reaction time is 15 hours. After the reaction is completed, cool to 78°C in vacuum, add water to separate the layers, and transfer the oil layer into a crude kettle.

[0071] (2) Crude preparation: Distill to 78°C under vacuum degree -0.09 MPa until there is no fraction. After nitrogen replacement, add 850 kg of industrial grade ethanol, reflux at 75°C to dissolve the clear solution, cool to 40°C and keep warm for 4 minutes, then cool to 10°C and centrifuge to obtain the crude product.

[0072] (3) Refining: pump in 850 kg of ethanol, add the crude product and reflux at 75 ° C to dissolve it, add 3 kg of activated carbon for adsorption for 40 minutes, and pass 0.6 m 3 / h nitrogen bubbling and stirring, hot filtration (precision 6μm, pressure 0.1MPa) and then reflux to dissolve the clear solution, cool to 40℃ and keep warm for 4min, then cool to 15℃ and centrifuge to obtain the fine product.

[0073] (4) Preparation of activated carbon:

[0074] c1) Crushing coconut shells into 2mm pieces, washing and drying to a moisture content of 3%;

[0075] c2) heating to 850°C and introducing 5 kg / h of steam for activation for 3 hours;

[0076] c3) Soak in 10% hydrochloric acid for 2 hours, wash and dry;

[0077] c4) crushing to 80 mesh;

[0078] c5) The mixture was immersed in a 5% silver nitrate ethanol solution at a solid-to-liquid ratio of 1:5, ultrasonically dispersed, allowed to stand, and filtered and dried to obtain activated carbon with a silver loading of 0.5%. The mixture was then treated with 80 mg / L ozone (flow rate 200 mL / min) for 1.5 hours and allowed to stand for 5 hours.

[0079] (5) Drying and packaging: Dry in hot water at 70℃ for 4 hours, internal pressure -0.095MPa, and package after passing the inspection.

[0080] Example 3

[0081] Specifically include:

[0082] (1) Condensation reaction: Heat to 70°C and maintain for 1 hour, then heat to 84°C, apply vacuum until distillate appears and start counting. When no distillate appears, heat to 92°C and keep warm for 4 hours. The total reaction time is 18 hours. After the reaction is completed, cool to 70°C in vacuum, add water to separate the layers, and transfer the oil layer into a crude kettle.

[0083] (2) Crude preparation: Distill to 80°C under vacuum degree -0.09 MPa until there is no fraction. After nitrogen replacement, add 950 kg of industrial grade ethanol, reflux at 78°C to dissolve the clear solution, cool to 45°C and keep warm for 3 minutes, then cool to 15°C and centrifuge to obtain the crude product.

[0084] (3) Refining: pump in 950 kg of ethanol, add the crude product and reflux at 78 ° C to dissolve it, add 5 kg of activated carbon for adsorption for 30 minutes, and pass 1.0 m 3 / h nitrogen bubbling and stirring, hot filtration (precision 10μm, pressure 0.2MPa) and then reflux to dissolve the clear solution, cool to 45℃ and keep warm for 3min, then cool to 20℃ and centrifuge to obtain the fine product.

[0085] (4) Preparation of activated carbon:

[0086] c1) Crushing coconut shells into 5mm pieces, washing and drying to a moisture content of 5%;

[0087] c2) heating to 870°C and introducing 8 kg / h of steam for activation for 2.5 hours;

[0088] c3) Soak in 12% hydrochloric acid for 2 hours, wash and dry;

[0089] c4) crushing to 120 mesh;

[0090] c5) The product was immersed in a 6% silver nitrate ethanol solution at a solid-to-liquid ratio of 1:6, ultrasonically dispersed, allowed to stand, and filtered and dried to obtain activated carbon with a silver loading of 1.0%. The product was then treated with 100 mg / L ozone (flow rate 300 mL / min) for 2.0 hours and allowed to stand for 4 hours.

[0091] (5) Drying and packaging: Dry in hot water at 80℃ for 4 hours, internal pressure -0.097MPa, and package after passing the test.

[0092] Example 4

[0093] Specifically include:

[0094] (1) Condensation reaction: Heat to 68°C and maintain for 1 hour, then heat to 83°C, apply vacuum until distillate appears and start counting. When no distillate appears, heat to 91°C and keep warm for 4 hours, with a total reaction time of 17 hours. After the reaction is completed, cool to 72°C in vacuum, add water to separate the layers, and transfer the oil layer into a crude reactor.

[0095] (2) Crude preparation: Distill at -0.09 MPa vacuum until no fraction is found at 79°C. After nitrogen replacement, add 920 kg of industrial-grade ethanol and reflux at 77°C to dissolve the clear solution. Cool to 43°C and keep warm for 3.5 min. Then cool to 13°C and centrifuge to obtain the crude product.

[0096] (3) Refining: Pump in 920 kg of ethanol, add the crude product and reflux at 77 ° C to dissolve it, add 4 kg of activated carbon for adsorption for 38 minutes, and pass 0.9 m 3 / h nitrogen bubbling and stirring, hot filtration (precision 7μm, pressure 0.18MPa) and then reflux to dissolve the clear solution, cool to 44℃ and keep warm for 3.5min, then cool to 17℃ and centrifuge to obtain the fine product.

[0097] (4) Preparation of activated carbon:

[0098] c1) Crushing coconut shells into 4mm pieces, washing and drying to a moisture content of 4.5%;

[0099] c2) heating to 865°C and introducing 7 kg / h of steam for activation for 2.7 hours;

[0100] c3) Soak in 11% hydrochloric acid for 2 hours, wash and dry;

[0101] c4) crushing to 90 mesh;

[0102] c5) The product was immersed in 5.2% silver nitrate ethanol solution at a solid-to-liquid ratio of 1:5.2, ultrasonically dispersed, allowed to stand, and filtered and dried to obtain activated carbon with a silver loading of 0.7%. The product was then treated with 85 mg / L ozone (flow rate 220 mL / min) for 1.7 hours and allowed to stand for 4.8 hours.

[0103] (5) Drying and packaging: Dry in hot water at 75℃ for 4 hours, internal pressure -0.096MPa, and package after passing the inspection.

[0104] Example 5

[0105] Specifically include:

[0106] (1) Condensation reaction: Heat to 66°C and maintain for 1 hour, then heat to 81°C, apply vacuum until distillate appears and start counting. When no distillate appears, heat to 89°C and keep warm for 4 hours, with a total reaction time of 16.5 hours. After the reaction is completed, cool to 76°C in vacuum, add water to separate the layers, and transfer the oil layer into a crude reactor.

[0107] (2) Crude preparation: Distill at -0.09 MPa vacuum until no fraction is found at 79°C. After nitrogen replacement, add 880 kg of industrial-grade ethanol, reflux at 76.5°C to dissolve the clear solution, cool to 44°C and keep warm for 3.2 min, then cool to 14°C and centrifuge to obtain the crude product.

[0108] (3) Refining: pump in 880 kg of ethanol, add the crude product and reflux at 76.5 ° C to dissolve it, add 3.5 kg of activated carbon for adsorption for 36 minutes, and pass 0.7 m 3 / h nitrogen bubbling and stirring, hot filtration (precision 9μm, pressure 0.12MPa) and then reflux to dissolve the clear solution, cool to 43.5℃ and keep warm for 3.2min, then cool to 16℃ and centrifuge to obtain the fine product.

[0109] (4) Preparation of activated carbon:

[0110] c1) Crushing coconut shells into 3.5mm pieces, washing and drying to a moisture content of 3.8%;

[0111] c2) heating to 862°C and introducing 6.5 kg / h steam for activation for 2.9 hours;

[0112] c3) Soak in 10.5% hydrochloric acid for 2 hours, wash and dry;

[0113] c4) crushing to 110 mesh;

[0114] c5) The product was immersed in 5.8% silver nitrate ethanol solution at a solid-to-liquid ratio of 1:5.8, ultrasonically dispersed, allowed to stand, and filtered and dried to obtain activated carbon with a silver loading of 0.9%. The product was then treated with 95 mg / L ozone (flow rate 280 mL / min) for 1.9 hours and allowed to stand for 4.2 hours.

[0115] (5) Drying and packaging: Dry in hot water at 68℃ for 4 hours, internal pressure -0.095MPa, and package after passing the test.

[0116] Comparative Example 1

[0117] Specifically include:

[0118] The method of Example 1 was adopted, except that the activated carbon modification step was omitted (only steps c1 to c4 were performed, and c5 was not performed).

[0119] (1) Preparation of activated carbon: Coconut shells were crushed to 3 mm, washed and dried, activated at high temperature (860 °C, 6 kg / h steam), purified by acid washing, and crushed to 100 mesh. Silver nitrate loading and ozone oxidation were not performed.

[0120] (2) The parameters of the remaining steps are exactly the same as those in Example 1.

[0121] Comparative Example 2

[0122] Specifically include:

[0123] The method of Example 1 was adopted, except that the high-temperature activation temperature was adjusted to 830°C.

[0124] (1) Preparation of activated carbon: In step c2, the temperature was raised to 830°C, and 6 kg / h of water vapor was introduced for activation for 2.8 hours. Ozone treatment was not performed. The remaining modification steps were the same as in Example 1.

[0125] (2) The parameters of the other steps are exactly the same as those in Example 1.

[0126] test

[0127] The purity of the etoclopramide products prepared in the examples and comparative examples was tested according to GB / T6283-2008, with 5 tests per group and the average value taken. The results are as follows:

[0128] Table 1

[0129] purity(%) Example 1 99.5 Example 2 99.3 Example 3 99.6 Example 4 99.4 Example 5 99.5 Comparative Example 1 94.2 Comparative Example 2 97.1

[0130] As can be seen from Table 1, the etocrilin product prepared by the method of the present invention has high purity.

[0131] The yields of etocrylene prepared by the methods of the examples and comparative examples were statistically analyzed and compared, and calculated based on the amount of acetic acid fed. The results are as follows:

[0132] Table 2

[0133] Yield (%) Example 1 88.5 Example 2 87.2 Example 3 89.0 Example 4 88.1 Example 5 88.8 Comparative Example 1 81.5 Comparative Example 2 86.0

[0134] As can be seen from Table 2, the yield of the etocrilin product prepared by the method of the present invention is relatively high.

[0135] The adsorption capacity of the activated carbon in Example 1 and the comparative example was tested for methylene blue adsorption value, referring to GB / T12496.10-1999, and the results are as follows:

[0136] Table 3

[0137] Methylene blue adsorption value (mg / g) Example 1 1200 Comparative Example 1 850 Comparative Example 2 1090

[0138] As can be seen from Table 3, the activated carbon used in the present invention has excellent adsorption capacity, thereby being able to better improve the purity of the etoclopramide product.

[0139] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing etocrylene, characterized in that: The process includes condensation reaction, crude preparation, refining, drying and packaging steps: Condensation reaction: Add acetic acid, ethyl cyanoacetate, benzophenone and ammonium acetate to an enameled reactor, first heat up for pre-reaction, then heat up and apply vacuum until distillation appears on the condenser, then start counting. When no distillation appears, continue heating and keep warm for reaction. The total reaction time is 15-18 hours. After the reaction is completed, cool down under vacuum, add water, stir and separate the layers, and transfer the oil layer to a crude reactor. Crude preparation: Distill under vacuum until there is no fraction, replace with nitrogen, add industrial-grade ethanol, reflux to dissolve, cool in sections, and centrifuge to obtain the crude product; Refining: Pump ethanol into the refining kettle, add the crude product, heat and reflux to dissolve, add pharmaceutical grade activated carbon for adsorption, introduce nitrogen for bubbling and stirring, filter hot and reflux to dissolve, cool in stages, and centrifuge to obtain the refined product; Drying and packaging: Drying is carried out in a double-cone dryer with hot water circulation, and the internal pressure of the dryer is controlled. The finished product is packaged after passing the inspection.

2. The preparation method according to claim 1, characterized in that The amount of each raw material added in the condensation reaction is: 150kg acetic acid, 360kg ethyl cyanoacetate, 550kg benzophenone and 50kg ammonium acetate; The temperature of the pre-reaction stage of the condensation reaction is 60-70°C and maintained for 1 hour; The main reaction stage of the condensation reaction is first heated to 80-84°C, and a vacuum of -0.088 MPa is applied. After there is no fraction, the temperature is raised to 88-92°C and kept for reaction for 4 hours; After the condensation reaction is completed, the temperature is lowered to below 80° C. in a vacuum environment, and 400 kg of water is added, stirred, and separated into layers.

3. The preparation method according to claim 1, characterized in that The crude step is distilled at -0.09 MPa vacuum to 78-80°C without distillate, and after nitrogen replacement, 900±50 kg of industrial grade ethanol is added; The stepwise cooling process of the roughing step is: firstly cooling to 40-45°C, keeping warm for 3-4 minutes, and then cooling to 10-15°C.

4. The preparation method according to claim 1, characterized in that In the refining step, 900±50kg of ethanol is pumped into the refining kettle, and the temperature is raised to 75-78°C to reflux and dissolve; In the refining step, 3-5 kg ​​of pharmaceutical grade activated carbon is added for adsorption for 30-40 minutes, and nitrogen gas with a flow rate of 0.6-1.0 m³ / h is simultaneously introduced for bubbling and stirring; The hot filtration accuracy of the refining step is 6-10 μm, and the filtration pressure is maintained at 0.1-0.2 MPa; The stepwise cooling process of the refining step is: firstly cooling to 40-45°C, keeping warm for 3-4 minutes, and then cooling to 15-20°C.

5. The preparation method according to claim 4, characterized in that The preparation method of the pharmaceutical grade activated carbon comprises the following steps: Raw material pretreatment: crush coconut shells to a particle size of 2-5 mm, wash with deionized water three times to remove impurities, and dry at 120°C until the moisture content is less than 5%; High-temperature activation: The pretreated coconut shells are fed into a rotary kiln and heated at 10°C / min to 850-870°C in a nitrogen atmosphere. Steam is introduced for activation for 2.5-3 hours, during which the pressure in the kiln is maintained at -0.01 MPa to obtain the activated product. Acid washing and purification: After cooling the activated product, soak it in 10-12% hydrochloric acid solution for 2 hours, filter it, wash it with deionized water until it is neutral, and dry it at 150°C for 6 hours; Crushing and screening: After drying, the material is crushed to 80-120 mesh, magnetic separation is used to remove ferromagnetic impurities, and sealed and packaged for later use.

6. The preparation method according to claim 5, characterized in that The water vapor flow rate is 5-8 kg / h.

7. The preparation method according to claim 5, characterized in that The pharmaceutical grade activated carbon is modified as follows: Silver nitrate loading modification: Pharmaceutical grade activated carbon was immersed in a 5-6% silver nitrate ethanol solution, ultrasonically dispersed for 30 minutes, and then allowed to stand for 2 hours. After filtration, it was vacuum-dried at 120°C for 3 hours to obtain a preliminary modified activated carbon with a silver loading of 0.5-1.0%. Ozone oxidation modification: Place the preliminarily modified activated carbon in a reactor, introduce ozone gas with an ozone concentration of 80-100 mg / L, treat at room temperature for 1.5-2 hours, maintain a gas flow rate of 200-300 mL / min, then discharge the material and let it stand for 4-5 hours to obtain.

8. The preparation method according to claim 7, characterized in that The solid-to-liquid ratio of the pharmaceutical-grade activated carbon and the silver nitrate ethanol solution is 1:5-6.

9. The preparation method according to claim 7, characterized in that The frequency of the ultrasonic dispersion is 40kHz and the power is 600W; The vacuum degree of the vacuum drying is 0.1 Pa.

10. The preparation method according to claim 1, characterized in that The drying step is carried out in a 2000L double cone dryer, using 60-80℃ hot water circulation drying for 4 hours, and the internal pressure of the dryer is controlled to be ≤-0.095MPa; The finished product testing standard is loss on drying ≤ 0.5%.

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