| 16.2 kg |
With dihydrogen peroxide; vanadium pentoxide In ethanol at 16 - 65℃; Large scale; |
1.2; 1.3; 2.2; 2.3; 3.2; 3.3; 4.2; 4.3 step (2) The preparation of lansoprazole crude product
The preparation of step (2) lansoprazole crude productThe solid dry matter lansoprazole sulfide and vanadium pentoxide are added to the ethanol solvent, and after the reaction is stirred for 20-30 min at a temperature of 50 ° C, the temperature is lowered to below 25 ° C, and hydrogen peroxide with a concentration of 30% is added, and at 40 ° C. After stirring the reaction for 1.5°C, TLC monitored the reaction end point, cooled to 0°C, crystallized, and centrifuged to dry to obtain crude lansoprazole;Specific operation process The preparation and preparation of the solution:Preparation of sodium thiosulfate solution: 1.6 kg of sodium thiosulfate was added to 4.9 kg of purified water, and stirred to dissolve for later use.Preparation of sodium carbonate solution: take 55.0 g of anhydrous sodium carbonate, add it to 147.0 kg of purified water, and stir to dissolve for later use. Preparation of cold ethanol: Weigh 6.1 kg of ethanol and cool it to below 10°C for later use.Oxidation reaction:300L stainless steel reactor under stirring (rotation controller reading is 12.0-16.0Hz, corresponding rotating speed 48-64r/min.) Add ethanol 97.65kg, lansoprazole sulfide (intermediate I) 21.7kg, vanadium pentoxide 217.0g.After feeding, heat to 30-65°C, keep warm, and stir (the reading of the speed controller is 12.0-16.0Hz, corresponding to the speed of 48-64r/min.) for 20-30min.The system was cooled to below 25°C, and 6.51 kg of 30% hydrogen peroxide was slowly added.After the addition of materials, the temperature is controlled at 16-55°C and the reaction is stirred for about 1-3h.(After 1.5 hours of reaction, samples were taken every 10-15 minutes, and the reaction was monitored by TLC.)Note: With the progress of the reaction, a large amount of products are precipitated and attached to the wall of the kettle, which affects the heat transfer.At this time, it is necessary to stop stirring, and use a steel shovel to disperse the product adhering to the kettle wall in the kettle and continue the reaction.Monitoring of the reaction end point: take about 0.25 ml of the reaction solution, add an appropriate amount of ethyl acetate to dilute to about 1.0 ml, shake well, and use it as the test solution; take about 30 mg of lansoprazole sulfide, add about 10 ml of ethyl acetate to make the solution. dissolved as a control solution.Draw 2-5ul of each of the above two solutions, respectively, point them on the same silica gel GF254 thin-layer plate, use petroleum ether (60-90):ethyl acetate (1:2) as the developing agent, develop, and place the ultraviolet light Viewed under light (254nm).The size and brightness of the lansoprazole sulfide spot in the chromatogram of the test product are not greater than that of the lansoprazole sulfide spot in the control solution, and the reaction end point is reached.Post-processing:Stirring speed: the reading of the speed controller is 12.0-16.0Hz, corresponding to the speed of 48-64r/min.Add 6.5kg of sodium thiosulfate solution to the above reaction system under stirring, cool down to 0-5°C, keep stirring for 1 hour for crystallization, under stirring, slowly discharge material into the centrifuge (the working mode of the centrifuge is high speed), put After the material is finished, centrifuge (the centrifuge working mode is high speed) for 10-15min.Rinse the filter cake with 6.1kg of cold ethanol and centrifuge (centrifuge working mode is high speed) for about 10-15min.The full amount of sodium carbonate solution was added to the 300L reaction kettle, and then the filter cake was transferred to the kettle for stirring and dispersion for 10-15min.In the stirring state, slowly discharge the material into the centrifuge for centrifugation (the working mode of the centrifuge is high speed), and continue to centrifuge (the working mode of the centrifuge is high speed) after the discharge is completed for 1-1.5h to obtain the wet weight of the crude lansoprazole product. About 31.6kg (after deducting the loss on drying, the crude lansoprazole is converted to about 21.6kg).The preparation of step (3) lansoprazole fine product The crude lansoprazole was added to the mixture of ethanol, acetone, disodium EDTA, purified water and ammonia water, wherein vacuum crystallization was performed at 30°C, centrifugal filtration, washing and drying were performed to obtain lansoprazole Excellent product; the density of ethanol is 0.81g/ml; the density of acetone is 0.79g/ml; the density of ammonia water is 0.91g/ml; the molar ratio of the added amount of disodium EDTA to the catalyst vanadium pentoxide is 1:1.The specific process is:The preparation of the solution:The preparation of the mixed solution: 2.6 kg of ethanol, 3.8 kg of acetone, and 1.6 kg of purified water are mixed, stirred evenly, and cooled to below 10° C. for later use.Preparation of sodium carbonate solution: add 37.0 g of anhydrous sodium carbonate, add 100.0 kg of purified water, and stir to dissolve for later use.Dissolve:Stirring speed: the reading of the speed controller is 20.0-25.0Hz, corresponding to the speed of 80-100r/min.64.8kg of ethanol, 94.6kg of acetone, 28.4kg of purified water (40kg minus 11.6kg of wet product moisture content) and 444.0g of disodium EDTA were added to the 300L stainless steel reaction kettle under stirring.Replace the air in the kettle with nitrogen once (cover the feeding port, open the vacuum valve, draw out the air in the kettle until the vacuum gauge shows 0.04-0.06MPa, close the vacuum valve, open the nitrogen valve and let in nitrogen until the reading of the vacuum gauge returns to zero).20.0 kg of lansoprazole crude product was added under the condition of nitrogen positive pressure, and the air in the kettle was replaced 3 times according to the above-mentioned operation mode.Put 2.96kg of ammonia water in the stainless steel feeding tank and add it into the reaction kettle, heat up to 30°C and stir until it is dissolved, and after the solution is clear, control the temperature (15-38°C) and continue to stir for 15-20min. Filtration and crystallization:Replace the 300L reaction kettle with nitrogen once (open the vacuum valve of the crystallization kettle, draw out the air in the kettle, until the vacuum gauge shows 0.06-0.08MPa, close the vacuum valve of the crystallization kettle, open the nitrogen valve and let in nitrogen until the reading of the vacuum gauge returns to zero), gas After the replacement is complete,Online filtration (the filter housing is stainless steel, the filter element material is PTFE, the pore size is 0.22um, and it is disposable), and the filtrate is pumped under stirring (the reading of the speed controller is 20.0-25.0Hz, and the corresponding speed is 80-100r/min.) ) in a 300L reaction kettle, cooled to 0 °C, and stirred for crystallization for 2 h under nitrogen protection. Centrifugation and post-processing: (this process uses two centrifuges to process at the same time)Stirring speed: The reading of the revolution controller is 20.0-25.0Hz, and the corresponding rotation speed is 80-100r/min.After the crystallization is completed, in a stirring state, slowly discharge the material to the two open centrifuges for centrifugation (the rotation speed is greater than 1500r/min).The filter cakes were rinsed with 2.0kg of mixed solution below 10°C in the centrifugal state respectively. After feeding, continue centrifugation (rotation speed greater than 1500r/min) for 10-15min to collect the filter cakes.60.0kg of sodium carbonate solution was added into the cleaned 300L reaction kettle, and the filter cake was transferred to the kettle for stirring and dispersing for 10-15min.In the stirring state, slowly discharge the material to the two open centrifuges for centrifugation (the speed is greater than 1500r/min).The filter cake is first rinsed with 20.0kg of sodium carbonate solution under centrifugal state, and then rinsed with 2.0kg of mixed solution. After feeding, continue to be centrifuged (the rotation speed is greater than 1500r/min) for 1-1.5 hours.The filter cake is collected and dispersed into a drying bag.Baking material:Dry under reduced pressure at 30-35°C (vacuum display 0.08--0.1MPa) for 3 hours, then heat up to 40-45°C under reduced pressure (vacuum display 0.08-0.1MPa) and dry, turn the material every 3 hours, and bake until moisture Below 0.5% (measured with a quick moisture meter).About 16.2kg of lansoprazole finished product is obtained by receiving the materials. |
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